Autocrine regulation of tumor cell repopulation by Hsp70-HMGB1 alarmin complex

Background Cancer recurrence is regulated by a variety of factors, among which is the material of dying tumor cells; it is suggested that remaining after anti-cancer therapy tumor cells receive a signal from proteins called damage-associated molecular patterns (DAMPs), one of which is heat shock protein 70 (Hsp70). Methods Two models of tumor repopulation were employed, based on minimal population of cancer cells and application of conditioned medium (CM). To deplete the CMs of Hsp70 affinity chromatography on ATP-agarose and immunoprecipitation were used. Cell proliferation and the dynamics of cell growth were measured using MTT assay and xCELLigence technology; cell growth markers were estimated using qPCR and with the aid of ELISA for prostaglandin E detection. Immunoprecipitation followed by mass-spectrometry was employed to identify Hsp70-binding proteins and protein-protein interaction assays were developed to reveal the above protein complexes. Results It was found that CM of dying tumor cells contains tumor regrowth-initiating factors and the removal of one of them, Hsp70, caused a reduction in the relapse-activating capacity. The pull out of Hsp70 alone using ATP-agarose had no effect on repopulation, while the immunodepletion of Hsp70 dramatically reduced its repopulation activity. Using proteomic and immunochemical approaches, we showed that Hsp70 in conditioned medium binds and binds another abundant alarmin, the High Mobility Group B1 (HMGB1) protein; the complex is formed in tumor cells treated with anti-cancer drugs, persists in the cytosol and is further released from dying tumor cells. Recurrence-activating power of Hsp70-HMGB1 complex was proved by the enhanced expression of proliferation markers, Ki67, Aurka and MCM-10 as well as by increase of prostaglandin E production and autophagy activation. Accordingly, dissociating the complex with Hsp70 chaperone inhibitors significantly inhibited the pro-growth effects of the above complex, in both in vitro and in vivo tumor relapse models. Conclusions These data led us to suggest that the abundance of the Hsp70-HMGB1 complex in the extracellular matrix may serve as a novel marker of relapse state in cancer patients, while specific targeting of the complex may be promising in the treatment of cancers with a high risk of recurrence. Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Sverchinsky, Dmitry V. [verfasserIn] Alhasan, Bashar A. Mikeladze, Marina A. Lazarev, Vladimir F. Kuznetcova, Liubov S. Morshneva, Alisa V. Nikotina, Alina D. Ziewanah, Amr Koludarova, Lidia V. Starkova, Tatiana Y. Margulis, Boris A. Guzhova, Irina V.

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2023

Schlagwörter:	Tumor relapse Alarmins Hsp70 HMGB1 Protein complex

Anmerkung:	© The Author(s) 2023

Übergeordnetes Werk:	Enthalten in: Journal of experimental & clinical cancer research - Berlin : Springer, 2008, 42(2023), 1 vom: 25. Okt.
Übergeordnetes Werk:	volume:42 ; year:2023 ; number:1 ; day:25 ; month:10

Links:	Volltext

DOI / URN:	10.1186/s13046-023-02857-0

Katalog-ID:	SPR053525728

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520			\|a Background Cancer recurrence is regulated by a variety of factors, among which is the material of dying tumor cells; it is suggested that remaining after anti-cancer therapy tumor cells receive a signal from proteins called damage-associated molecular patterns (DAMPs), one of which is heat shock protein 70 (Hsp70). Methods Two models of tumor repopulation were employed, based on minimal population of cancer cells and application of conditioned medium (CM). To deplete the CMs of Hsp70 affinity chromatography on ATP-agarose and immunoprecipitation were used. Cell proliferation and the dynamics of cell growth were measured using MTT assay and xCELLigence technology; cell growth markers were estimated using qPCR and with the aid of ELISA for prostaglandin E detection. Immunoprecipitation followed by mass-spectrometry was employed to identify Hsp70-binding proteins and protein-protein interaction assays were developed to reveal the above protein complexes. Results It was found that CM of dying tumor cells contains tumor regrowth-initiating factors and the removal of one of them, Hsp70, caused a reduction in the relapse-activating capacity. The pull out of Hsp70 alone using ATP-agarose had no effect on repopulation, while the immunodepletion of Hsp70 dramatically reduced its repopulation activity. Using proteomic and immunochemical approaches, we showed that Hsp70 in conditioned medium binds and binds another abundant alarmin, the High Mobility Group B1 (HMGB1) protein; the complex is formed in tumor cells treated with anti-cancer drugs, persists in the cytosol and is further released from dying tumor cells. Recurrence-activating power of Hsp70-HMGB1 complex was proved by the enhanced expression of proliferation markers, Ki67, Aurka and MCM-10 as well as by increase of prostaglandin E production and autophagy activation. Accordingly, dissociating the complex with Hsp70 chaperone inhibitors significantly inhibited the pro-growth effects of the above complex, in both in vitro and in vivo tumor relapse models. Conclusions These data led us to suggest that the abundance of the Hsp70-HMGB1 complex in the extracellular matrix may serve as a novel marker of relapse state in cancer patients, while specific targeting of the complex may be promising in the treatment of cancers with a high risk of recurrence.
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allfields	10.1186/s13046-023-02857-0 doi (DE-627)SPR053525728 (SPR)s13046-023-02857-0-e DE-627 ger DE-627 rakwb eng Sverchinsky, Dmitry V. verfasserin aut Autocrine regulation of tumor cell repopulation by Hsp70-HMGB1 alarmin complex 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2023 Background Cancer recurrence is regulated by a variety of factors, among which is the material of dying tumor cells; it is suggested that remaining after anti-cancer therapy tumor cells receive a signal from proteins called damage-associated molecular patterns (DAMPs), one of which is heat shock protein 70 (Hsp70). Methods Two models of tumor repopulation were employed, based on minimal population of cancer cells and application of conditioned medium (CM). To deplete the CMs of Hsp70 affinity chromatography on ATP-agarose and immunoprecipitation were used. Cell proliferation and the dynamics of cell growth were measured using MTT assay and xCELLigence technology; cell growth markers were estimated using qPCR and with the aid of ELISA for prostaglandin E detection. Immunoprecipitation followed by mass-spectrometry was employed to identify Hsp70-binding proteins and protein-protein interaction assays were developed to reveal the above protein complexes. Results It was found that CM of dying tumor cells contains tumor regrowth-initiating factors and the removal of one of them, Hsp70, caused a reduction in the relapse-activating capacity. The pull out of Hsp70 alone using ATP-agarose had no effect on repopulation, while the immunodepletion of Hsp70 dramatically reduced its repopulation activity. Using proteomic and immunochemical approaches, we showed that Hsp70 in conditioned medium binds and binds another abundant alarmin, the High Mobility Group B1 (HMGB1) protein; the complex is formed in tumor cells treated with anti-cancer drugs, persists in the cytosol and is further released from dying tumor cells. Recurrence-activating power of Hsp70-HMGB1 complex was proved by the enhanced expression of proliferation markers, Ki67, Aurka and MCM-10 as well as by increase of prostaglandin E production and autophagy activation. Accordingly, dissociating the complex with Hsp70 chaperone inhibitors significantly inhibited the pro-growth effects of the above complex, in both in vitro and in vivo tumor relapse models. Conclusions These data led us to suggest that the abundance of the Hsp70-HMGB1 complex in the extracellular matrix may serve as a novel marker of relapse state in cancer patients, while specific targeting of the complex may be promising in the treatment of cancers with a high risk of recurrence. Tumor relapse (dpeaa)DE-He213 Alarmins (dpeaa)DE-He213 Hsp70 (dpeaa)DE-He213 HMGB1 (dpeaa)DE-He213 Protein complex (dpeaa)DE-He213 Alhasan, Bashar A. aut Mikeladze, Marina A. aut Lazarev, Vladimir F. aut Kuznetcova, Liubov S. aut Morshneva, Alisa V. aut Nikotina, Alina D. aut Ziewanah, Amr aut Koludarova, Lidia V. aut Starkova, Tatiana Y. aut Margulis, Boris A. aut Guzhova, Irina V. aut Enthalten in Journal of experimental & clinical cancer research Berlin : Springer, 2008 42(2023), 1 vom: 25. Okt. (DE-627)568921380 (DE-600)2430698-8 1756-9966 nnns volume:42 year:2023 number:1 day:25 month:10 https://dx.doi.org/10.1186/s13046-023-02857-0 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 42 2023 1 25 10
spelling	10.1186/s13046-023-02857-0 doi (DE-627)SPR053525728 (SPR)s13046-023-02857-0-e DE-627 ger DE-627 rakwb eng Sverchinsky, Dmitry V. verfasserin aut Autocrine regulation of tumor cell repopulation by Hsp70-HMGB1 alarmin complex 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2023 Background Cancer recurrence is regulated by a variety of factors, among which is the material of dying tumor cells; it is suggested that remaining after anti-cancer therapy tumor cells receive a signal from proteins called damage-associated molecular patterns (DAMPs), one of which is heat shock protein 70 (Hsp70). Methods Two models of tumor repopulation were employed, based on minimal population of cancer cells and application of conditioned medium (CM). To deplete the CMs of Hsp70 affinity chromatography on ATP-agarose and immunoprecipitation were used. Cell proliferation and the dynamics of cell growth were measured using MTT assay and xCELLigence technology; cell growth markers were estimated using qPCR and with the aid of ELISA for prostaglandin E detection. Immunoprecipitation followed by mass-spectrometry was employed to identify Hsp70-binding proteins and protein-protein interaction assays were developed to reveal the above protein complexes. Results It was found that CM of dying tumor cells contains tumor regrowth-initiating factors and the removal of one of them, Hsp70, caused a reduction in the relapse-activating capacity. The pull out of Hsp70 alone using ATP-agarose had no effect on repopulation, while the immunodepletion of Hsp70 dramatically reduced its repopulation activity. Using proteomic and immunochemical approaches, we showed that Hsp70 in conditioned medium binds and binds another abundant alarmin, the High Mobility Group B1 (HMGB1) protein; the complex is formed in tumor cells treated with anti-cancer drugs, persists in the cytosol and is further released from dying tumor cells. Recurrence-activating power of Hsp70-HMGB1 complex was proved by the enhanced expression of proliferation markers, Ki67, Aurka and MCM-10 as well as by increase of prostaglandin E production and autophagy activation. Accordingly, dissociating the complex with Hsp70 chaperone inhibitors significantly inhibited the pro-growth effects of the above complex, in both in vitro and in vivo tumor relapse models. Conclusions These data led us to suggest that the abundance of the Hsp70-HMGB1 complex in the extracellular matrix may serve as a novel marker of relapse state in cancer patients, while specific targeting of the complex may be promising in the treatment of cancers with a high risk of recurrence. Tumor relapse (dpeaa)DE-He213 Alarmins (dpeaa)DE-He213 Hsp70 (dpeaa)DE-He213 HMGB1 (dpeaa)DE-He213 Protein complex (dpeaa)DE-He213 Alhasan, Bashar A. aut Mikeladze, Marina A. aut Lazarev, Vladimir F. aut Kuznetcova, Liubov S. aut Morshneva, Alisa V. aut Nikotina, Alina D. aut Ziewanah, Amr aut Koludarova, Lidia V. aut Starkova, Tatiana Y. aut Margulis, Boris A. aut Guzhova, Irina V. aut Enthalten in Journal of experimental & clinical cancer research Berlin : Springer, 2008 42(2023), 1 vom: 25. Okt. (DE-627)568921380 (DE-600)2430698-8 1756-9966 nnns volume:42 year:2023 number:1 day:25 month:10 https://dx.doi.org/10.1186/s13046-023-02857-0 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 42 2023 1 25 10
allfields_unstemmed	10.1186/s13046-023-02857-0 doi (DE-627)SPR053525728 (SPR)s13046-023-02857-0-e DE-627 ger DE-627 rakwb eng Sverchinsky, Dmitry V. verfasserin aut Autocrine regulation of tumor cell repopulation by Hsp70-HMGB1 alarmin complex 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2023 Background Cancer recurrence is regulated by a variety of factors, among which is the material of dying tumor cells; it is suggested that remaining after anti-cancer therapy tumor cells receive a signal from proteins called damage-associated molecular patterns (DAMPs), one of which is heat shock protein 70 (Hsp70). Methods Two models of tumor repopulation were employed, based on minimal population of cancer cells and application of conditioned medium (CM). To deplete the CMs of Hsp70 affinity chromatography on ATP-agarose and immunoprecipitation were used. Cell proliferation and the dynamics of cell growth were measured using MTT assay and xCELLigence technology; cell growth markers were estimated using qPCR and with the aid of ELISA for prostaglandin E detection. Immunoprecipitation followed by mass-spectrometry was employed to identify Hsp70-binding proteins and protein-protein interaction assays were developed to reveal the above protein complexes. Results It was found that CM of dying tumor cells contains tumor regrowth-initiating factors and the removal of one of them, Hsp70, caused a reduction in the relapse-activating capacity. The pull out of Hsp70 alone using ATP-agarose had no effect on repopulation, while the immunodepletion of Hsp70 dramatically reduced its repopulation activity. Using proteomic and immunochemical approaches, we showed that Hsp70 in conditioned medium binds and binds another abundant alarmin, the High Mobility Group B1 (HMGB1) protein; the complex is formed in tumor cells treated with anti-cancer drugs, persists in the cytosol and is further released from dying tumor cells. Recurrence-activating power of Hsp70-HMGB1 complex was proved by the enhanced expression of proliferation markers, Ki67, Aurka and MCM-10 as well as by increase of prostaglandin E production and autophagy activation. Accordingly, dissociating the complex with Hsp70 chaperone inhibitors significantly inhibited the pro-growth effects of the above complex, in both in vitro and in vivo tumor relapse models. Conclusions These data led us to suggest that the abundance of the Hsp70-HMGB1 complex in the extracellular matrix may serve as a novel marker of relapse state in cancer patients, while specific targeting of the complex may be promising in the treatment of cancers with a high risk of recurrence. Tumor relapse (dpeaa)DE-He213 Alarmins (dpeaa)DE-He213 Hsp70 (dpeaa)DE-He213 HMGB1 (dpeaa)DE-He213 Protein complex (dpeaa)DE-He213 Alhasan, Bashar A. aut Mikeladze, Marina A. aut Lazarev, Vladimir F. aut Kuznetcova, Liubov S. aut Morshneva, Alisa V. aut Nikotina, Alina D. aut Ziewanah, Amr aut Koludarova, Lidia V. aut Starkova, Tatiana Y. aut Margulis, Boris A. aut Guzhova, Irina V. aut Enthalten in Journal of experimental & clinical cancer research Berlin : Springer, 2008 42(2023), 1 vom: 25. Okt. (DE-627)568921380 (DE-600)2430698-8 1756-9966 nnns volume:42 year:2023 number:1 day:25 month:10 https://dx.doi.org/10.1186/s13046-023-02857-0 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 42 2023 1 25 10
allfieldsGer	10.1186/s13046-023-02857-0 doi (DE-627)SPR053525728 (SPR)s13046-023-02857-0-e DE-627 ger DE-627 rakwb eng Sverchinsky, Dmitry V. verfasserin aut Autocrine regulation of tumor cell repopulation by Hsp70-HMGB1 alarmin complex 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2023 Background Cancer recurrence is regulated by a variety of factors, among which is the material of dying tumor cells; it is suggested that remaining after anti-cancer therapy tumor cells receive a signal from proteins called damage-associated molecular patterns (DAMPs), one of which is heat shock protein 70 (Hsp70). Methods Two models of tumor repopulation were employed, based on minimal population of cancer cells and application of conditioned medium (CM). To deplete the CMs of Hsp70 affinity chromatography on ATP-agarose and immunoprecipitation were used. Cell proliferation and the dynamics of cell growth were measured using MTT assay and xCELLigence technology; cell growth markers were estimated using qPCR and with the aid of ELISA for prostaglandin E detection. Immunoprecipitation followed by mass-spectrometry was employed to identify Hsp70-binding proteins and protein-protein interaction assays were developed to reveal the above protein complexes. Results It was found that CM of dying tumor cells contains tumor regrowth-initiating factors and the removal of one of them, Hsp70, caused a reduction in the relapse-activating capacity. The pull out of Hsp70 alone using ATP-agarose had no effect on repopulation, while the immunodepletion of Hsp70 dramatically reduced its repopulation activity. Using proteomic and immunochemical approaches, we showed that Hsp70 in conditioned medium binds and binds another abundant alarmin, the High Mobility Group B1 (HMGB1) protein; the complex is formed in tumor cells treated with anti-cancer drugs, persists in the cytosol and is further released from dying tumor cells. Recurrence-activating power of Hsp70-HMGB1 complex was proved by the enhanced expression of proliferation markers, Ki67, Aurka and MCM-10 as well as by increase of prostaglandin E production and autophagy activation. Accordingly, dissociating the complex with Hsp70 chaperone inhibitors significantly inhibited the pro-growth effects of the above complex, in both in vitro and in vivo tumor relapse models. Conclusions These data led us to suggest that the abundance of the Hsp70-HMGB1 complex in the extracellular matrix may serve as a novel marker of relapse state in cancer patients, while specific targeting of the complex may be promising in the treatment of cancers with a high risk of recurrence. Tumor relapse (dpeaa)DE-He213 Alarmins (dpeaa)DE-He213 Hsp70 (dpeaa)DE-He213 HMGB1 (dpeaa)DE-He213 Protein complex (dpeaa)DE-He213 Alhasan, Bashar A. aut Mikeladze, Marina A. aut Lazarev, Vladimir F. aut Kuznetcova, Liubov S. aut Morshneva, Alisa V. aut Nikotina, Alina D. aut Ziewanah, Amr aut Koludarova, Lidia V. aut Starkova, Tatiana Y. aut Margulis, Boris A. aut Guzhova, Irina V. aut Enthalten in Journal of experimental & clinical cancer research Berlin : Springer, 2008 42(2023), 1 vom: 25. Okt. (DE-627)568921380 (DE-600)2430698-8 1756-9966 nnns volume:42 year:2023 number:1 day:25 month:10 https://dx.doi.org/10.1186/s13046-023-02857-0 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 42 2023 1 25 10
allfieldsSound	10.1186/s13046-023-02857-0 doi (DE-627)SPR053525728 (SPR)s13046-023-02857-0-e DE-627 ger DE-627 rakwb eng Sverchinsky, Dmitry V. verfasserin aut Autocrine regulation of tumor cell repopulation by Hsp70-HMGB1 alarmin complex 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2023 Background Cancer recurrence is regulated by a variety of factors, among which is the material of dying tumor cells; it is suggested that remaining after anti-cancer therapy tumor cells receive a signal from proteins called damage-associated molecular patterns (DAMPs), one of which is heat shock protein 70 (Hsp70). Methods Two models of tumor repopulation were employed, based on minimal population of cancer cells and application of conditioned medium (CM). To deplete the CMs of Hsp70 affinity chromatography on ATP-agarose and immunoprecipitation were used. Cell proliferation and the dynamics of cell growth were measured using MTT assay and xCELLigence technology; cell growth markers were estimated using qPCR and with the aid of ELISA for prostaglandin E detection. Immunoprecipitation followed by mass-spectrometry was employed to identify Hsp70-binding proteins and protein-protein interaction assays were developed to reveal the above protein complexes. Results It was found that CM of dying tumor cells contains tumor regrowth-initiating factors and the removal of one of them, Hsp70, caused a reduction in the relapse-activating capacity. The pull out of Hsp70 alone using ATP-agarose had no effect on repopulation, while the immunodepletion of Hsp70 dramatically reduced its repopulation activity. Using proteomic and immunochemical approaches, we showed that Hsp70 in conditioned medium binds and binds another abundant alarmin, the High Mobility Group B1 (HMGB1) protein; the complex is formed in tumor cells treated with anti-cancer drugs, persists in the cytosol and is further released from dying tumor cells. Recurrence-activating power of Hsp70-HMGB1 complex was proved by the enhanced expression of proliferation markers, Ki67, Aurka and MCM-10 as well as by increase of prostaglandin E production and autophagy activation. Accordingly, dissociating the complex with Hsp70 chaperone inhibitors significantly inhibited the pro-growth effects of the above complex, in both in vitro and in vivo tumor relapse models. Conclusions These data led us to suggest that the abundance of the Hsp70-HMGB1 complex in the extracellular matrix may serve as a novel marker of relapse state in cancer patients, while specific targeting of the complex may be promising in the treatment of cancers with a high risk of recurrence. Tumor relapse (dpeaa)DE-He213 Alarmins (dpeaa)DE-He213 Hsp70 (dpeaa)DE-He213 HMGB1 (dpeaa)DE-He213 Protein complex (dpeaa)DE-He213 Alhasan, Bashar A. aut Mikeladze, Marina A. aut Lazarev, Vladimir F. aut Kuznetcova, Liubov S. aut Morshneva, Alisa V. aut Nikotina, Alina D. aut Ziewanah, Amr aut Koludarova, Lidia V. aut Starkova, Tatiana Y. aut Margulis, Boris A. aut Guzhova, Irina V. aut Enthalten in Journal of experimental & clinical cancer research Berlin : Springer, 2008 42(2023), 1 vom: 25. Okt. (DE-627)568921380 (DE-600)2430698-8 1756-9966 nnns volume:42 year:2023 number:1 day:25 month:10 https://dx.doi.org/10.1186/s13046-023-02857-0 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 42 2023 1 25 10
language	English
source	Enthalten in Journal of experimental & clinical cancer research 42(2023), 1 vom: 25. Okt. volume:42 year:2023 number:1 day:25 month:10
sourceStr	Enthalten in Journal of experimental & clinical cancer research 42(2023), 1 vom: 25. Okt. volume:42 year:2023 number:1 day:25 month:10
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	Tumor relapse Alarmins Hsp70 HMGB1 Protein complex
isfreeaccess_bool	true
container_title	Journal of experimental & clinical cancer research
authorswithroles_txt_mv	Sverchinsky, Dmitry V. @@aut@@ Alhasan, Bashar A. @@aut@@ Mikeladze, Marina A. @@aut@@ Lazarev, Vladimir F. @@aut@@ Kuznetcova, Liubov S. @@aut@@ Morshneva, Alisa V. @@aut@@ Nikotina, Alina D. @@aut@@ Ziewanah, Amr @@aut@@ Koludarova, Lidia V. @@aut@@ Starkova, Tatiana Y. @@aut@@ Margulis, Boris A. @@aut@@ Guzhova, Irina V. @@aut@@
publishDateDaySort_date	2023-10-25T00:00:00Z
hierarchy_top_id	568921380
id	SPR053525728
language_de	englisch
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Methods Two models of tumor repopulation were employed, based on minimal population of cancer cells and application of conditioned medium (CM). To deplete the CMs of Hsp70 affinity chromatography on ATP-agarose and immunoprecipitation were used. Cell proliferation and the dynamics of cell growth were measured using MTT assay and xCELLigence technology; cell growth markers were estimated using qPCR and with the aid of ELISA for prostaglandin E detection. Immunoprecipitation followed by mass-spectrometry was employed to identify Hsp70-binding proteins and protein-protein interaction assays were developed to reveal the above protein complexes. Results It was found that CM of dying tumor cells contains tumor regrowth-initiating factors and the removal of one of them, Hsp70, caused a reduction in the relapse-activating capacity. The pull out of Hsp70 alone using ATP-agarose had no effect on repopulation, while the immunodepletion of Hsp70 dramatically reduced its repopulation activity. Using proteomic and immunochemical approaches, we showed that Hsp70 in conditioned medium binds and binds another abundant alarmin, the High Mobility Group B1 (HMGB1) protein; the complex is formed in tumor cells treated with anti-cancer drugs, persists in the cytosol and is further released from dying tumor cells. Recurrence-activating power of Hsp70-HMGB1 complex was proved by the enhanced expression of proliferation markers, Ki67, Aurka and MCM-10 as well as by increase of prostaglandin E production and autophagy activation. Accordingly, dissociating the complex with Hsp70 chaperone inhibitors significantly inhibited the pro-growth effects of the above complex, in both in vitro and in vivo tumor relapse models. 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author	Sverchinsky, Dmitry V.
spellingShingle	Sverchinsky, Dmitry V. misc Tumor relapse misc Alarmins misc Hsp70 misc HMGB1 misc Protein complex Autocrine regulation of tumor cell repopulation by Hsp70-HMGB1 alarmin complex
authorStr	Sverchinsky, Dmitry V.
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topic_title	Autocrine regulation of tumor cell repopulation by Hsp70-HMGB1 alarmin complex Tumor relapse (dpeaa)DE-He213 Alarmins (dpeaa)DE-He213 Hsp70 (dpeaa)DE-He213 HMGB1 (dpeaa)DE-He213 Protein complex (dpeaa)DE-He213
topic	misc Tumor relapse misc Alarmins misc Hsp70 misc HMGB1 misc Protein complex
topic_unstemmed	misc Tumor relapse misc Alarmins misc Hsp70 misc HMGB1 misc Protein complex
topic_browse	misc Tumor relapse misc Alarmins misc Hsp70 misc HMGB1 misc Protein complex
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title	Autocrine regulation of tumor cell repopulation by Hsp70-HMGB1 alarmin complex
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title_full	Autocrine regulation of tumor cell repopulation by Hsp70-HMGB1 alarmin complex
author_sort	Sverchinsky, Dmitry V.
journal	Journal of experimental & clinical cancer research
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author_browse	Sverchinsky, Dmitry V. Alhasan, Bashar A. Mikeladze, Marina A. Lazarev, Vladimir F. Kuznetcova, Liubov S. Morshneva, Alisa V. Nikotina, Alina D. Ziewanah, Amr Koludarova, Lidia V. Starkova, Tatiana Y. Margulis, Boris A. Guzhova, Irina V.
container_volume	42
format_se	Elektronische Aufsätze
author-letter	Sverchinsky, Dmitry V.
doi_str_mv	10.1186/s13046-023-02857-0
title_sort	autocrine regulation of tumor cell repopulation by hsp70-hmgb1 alarmin complex
title_auth	Autocrine regulation of tumor cell repopulation by Hsp70-HMGB1 alarmin complex
abstract	Background Cancer recurrence is regulated by a variety of factors, among which is the material of dying tumor cells; it is suggested that remaining after anti-cancer therapy tumor cells receive a signal from proteins called damage-associated molecular patterns (DAMPs), one of which is heat shock protein 70 (Hsp70). Methods Two models of tumor repopulation were employed, based on minimal population of cancer cells and application of conditioned medium (CM). To deplete the CMs of Hsp70 affinity chromatography on ATP-agarose and immunoprecipitation were used. Cell proliferation and the dynamics of cell growth were measured using MTT assay and xCELLigence technology; cell growth markers were estimated using qPCR and with the aid of ELISA for prostaglandin E detection. Immunoprecipitation followed by mass-spectrometry was employed to identify Hsp70-binding proteins and protein-protein interaction assays were developed to reveal the above protein complexes. Results It was found that CM of dying tumor cells contains tumor regrowth-initiating factors and the removal of one of them, Hsp70, caused a reduction in the relapse-activating capacity. The pull out of Hsp70 alone using ATP-agarose had no effect on repopulation, while the immunodepletion of Hsp70 dramatically reduced its repopulation activity. Using proteomic and immunochemical approaches, we showed that Hsp70 in conditioned medium binds and binds another abundant alarmin, the High Mobility Group B1 (HMGB1) protein; the complex is formed in tumor cells treated with anti-cancer drugs, persists in the cytosol and is further released from dying tumor cells. Recurrence-activating power of Hsp70-HMGB1 complex was proved by the enhanced expression of proliferation markers, Ki67, Aurka and MCM-10 as well as by increase of prostaglandin E production and autophagy activation. Accordingly, dissociating the complex with Hsp70 chaperone inhibitors significantly inhibited the pro-growth effects of the above complex, in both in vitro and in vivo tumor relapse models. Conclusions These data led us to suggest that the abundance of the Hsp70-HMGB1 complex in the extracellular matrix may serve as a novel marker of relapse state in cancer patients, while specific targeting of the complex may be promising in the treatment of cancers with a high risk of recurrence. © The Author(s) 2023
abstractGer	Background Cancer recurrence is regulated by a variety of factors, among which is the material of dying tumor cells; it is suggested that remaining after anti-cancer therapy tumor cells receive a signal from proteins called damage-associated molecular patterns (DAMPs), one of which is heat shock protein 70 (Hsp70). Methods Two models of tumor repopulation were employed, based on minimal population of cancer cells and application of conditioned medium (CM). To deplete the CMs of Hsp70 affinity chromatography on ATP-agarose and immunoprecipitation were used. Cell proliferation and the dynamics of cell growth were measured using MTT assay and xCELLigence technology; cell growth markers were estimated using qPCR and with the aid of ELISA for prostaglandin E detection. Immunoprecipitation followed by mass-spectrometry was employed to identify Hsp70-binding proteins and protein-protein interaction assays were developed to reveal the above protein complexes. Results It was found that CM of dying tumor cells contains tumor regrowth-initiating factors and the removal of one of them, Hsp70, caused a reduction in the relapse-activating capacity. The pull out of Hsp70 alone using ATP-agarose had no effect on repopulation, while the immunodepletion of Hsp70 dramatically reduced its repopulation activity. Using proteomic and immunochemical approaches, we showed that Hsp70 in conditioned medium binds and binds another abundant alarmin, the High Mobility Group B1 (HMGB1) protein; the complex is formed in tumor cells treated with anti-cancer drugs, persists in the cytosol and is further released from dying tumor cells. Recurrence-activating power of Hsp70-HMGB1 complex was proved by the enhanced expression of proliferation markers, Ki67, Aurka and MCM-10 as well as by increase of prostaglandin E production and autophagy activation. Accordingly, dissociating the complex with Hsp70 chaperone inhibitors significantly inhibited the pro-growth effects of the above complex, in both in vitro and in vivo tumor relapse models. Conclusions These data led us to suggest that the abundance of the Hsp70-HMGB1 complex in the extracellular matrix may serve as a novel marker of relapse state in cancer patients, while specific targeting of the complex may be promising in the treatment of cancers with a high risk of recurrence. © The Author(s) 2023
abstract_unstemmed	Background Cancer recurrence is regulated by a variety of factors, among which is the material of dying tumor cells; it is suggested that remaining after anti-cancer therapy tumor cells receive a signal from proteins called damage-associated molecular patterns (DAMPs), one of which is heat shock protein 70 (Hsp70). Methods Two models of tumor repopulation were employed, based on minimal population of cancer cells and application of conditioned medium (CM). To deplete the CMs of Hsp70 affinity chromatography on ATP-agarose and immunoprecipitation were used. Cell proliferation and the dynamics of cell growth were measured using MTT assay and xCELLigence technology; cell growth markers were estimated using qPCR and with the aid of ELISA for prostaglandin E detection. Immunoprecipitation followed by mass-spectrometry was employed to identify Hsp70-binding proteins and protein-protein interaction assays were developed to reveal the above protein complexes. Results It was found that CM of dying tumor cells contains tumor regrowth-initiating factors and the removal of one of them, Hsp70, caused a reduction in the relapse-activating capacity. The pull out of Hsp70 alone using ATP-agarose had no effect on repopulation, while the immunodepletion of Hsp70 dramatically reduced its repopulation activity. Using proteomic and immunochemical approaches, we showed that Hsp70 in conditioned medium binds and binds another abundant alarmin, the High Mobility Group B1 (HMGB1) protein; the complex is formed in tumor cells treated with anti-cancer drugs, persists in the cytosol and is further released from dying tumor cells. Recurrence-activating power of Hsp70-HMGB1 complex was proved by the enhanced expression of proliferation markers, Ki67, Aurka and MCM-10 as well as by increase of prostaglandin E production and autophagy activation. Accordingly, dissociating the complex with Hsp70 chaperone inhibitors significantly inhibited the pro-growth effects of the above complex, in both in vitro and in vivo tumor relapse models. Conclusions These data led us to suggest that the abundance of the Hsp70-HMGB1 complex in the extracellular matrix may serve as a novel marker of relapse state in cancer patients, while specific targeting of the complex may be promising in the treatment of cancers with a high risk of recurrence. © The Author(s) 2023
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title_short	Autocrine regulation of tumor cell repopulation by Hsp70-HMGB1 alarmin complex
url	https://dx.doi.org/10.1186/s13046-023-02857-0
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author2	Alhasan, Bashar A. Mikeladze, Marina A. Lazarev, Vladimir F. Kuznetcova, Liubov S. Morshneva, Alisa V. Nikotina, Alina D. Ziewanah, Amr Koludarova, Lidia V. Starkova, Tatiana Y. Margulis, Boris A. Guzhova, Irina V.
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Autocrine regulation of tumor cell repopulation by Hsp70-HMGB1 alarmin complex

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