CDK1 serves as a therapeutic target of adrenocortical carcinoma via regulating epithelial–mesenchymal transition, G2/M phase transition, and PANoptosis

Background Adrenocortical carcinoma (ACC) is an extremely rare, aggressive tumor with few effective therapeutic options or drugs. Mitotane (Mtn), which is the only authorized therapeutic drug, came out in 1970 and is still the only first-line treatment for ACC in spite of serious adverse reaction and a high recurrence rate. Methods By in silico analysis of the ACC dataset in the cancer genome atlas (TCGA), we determined that high expression levels of cyclin-dependent kinase-1 (CDK1) were significantly related to the adverse clinical outcomes of ACC. In vitro and in vivo experiments were performed to evaluate the role of CDK1 in ACC progression through gain and loss of function assays in ACC cells. CDK1 inhibitors were screened to identify potential candidates for the treatment of ACC. RNA sequencing, co-immunoprecipitation, and immunofluorescence assays were used to elucidate the mechanism. Results Overexpression of CDK1 in ACC cell lines promoted proliferation and induced the epithelial-to-mesenchymal transition (EMT), whereas knockdown of CDK1 expression inhibited growth of ACC cell lines. The CDK1 inhibitor, cucurbitacin E (CurE), had the best inhibitory effect with good time-and dose-dependent activity both in vitro and in vivo. CurE had a greater inhibitory effect on ACC xenografts in nude mice than mitotane, without obvious adverse effects. Most importantly, combined treatment with CurE and mitotane almost totally eliminated ACC tumors. With respect to mechanism, CDK1 facilitated the EMT of ACC cells via Slug and Twist and locked ACC cells into the G2/M checkpoint through interaction with UBE2C and AURKA/B. CDK1 also regulated pyroptosis, apoptosis, and necroptosis (PANoptosis) of ACC cells through binding with the PANoptosome in a ZBP1-dependent way. Conclusions CDK1 could be exploited as an essential therapeutic target of ACC via regulating the EMT, the G2/M checkpoint, and PANoptosis. Thus, CurE may be a potential candidate drug for ACC therapy with good safety and efficacy, which will meet the great need of patients with ACC. Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Ren, Liwen [verfasserIn] Yang, Yihui Li, Wan Zheng, Xiangjin Liu, Jinyi Li, Sha Yang, Hong Zhang, Yizhi Ge, Binbin Zhang, Sen Fu, Weiqi Dong, Dexin Du, Guanhua Wang, Jinhua

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2022

Schlagwörter:	Adrenocortical carcinoma CDK1 Cucurbitacin E Mitotane EMT Epithelial-mesenchymal transition PANoptosis

Anmerkung:	© The Author(s) 2022

Übergeordnetes Werk:	Enthalten in: Journal of translational medicine - London : BioMed Central, 2003, 20(2022), 1 vom: 02. Okt.
Übergeordnetes Werk:	volume:20 ; year:2022 ; number:1 ; day:02 ; month:10

Links:	Volltext

DOI / URN:	10.1186/s12967-022-03641-y

Katalog-ID:	SPR051031876

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520			\|a Background Adrenocortical carcinoma (ACC) is an extremely rare, aggressive tumor with few effective therapeutic options or drugs. Mitotane (Mtn), which is the only authorized therapeutic drug, came out in 1970 and is still the only first-line treatment for ACC in spite of serious adverse reaction and a high recurrence rate. Methods By in silico analysis of the ACC dataset in the cancer genome atlas (TCGA), we determined that high expression levels of cyclin-dependent kinase-1 (CDK1) were significantly related to the adverse clinical outcomes of ACC. In vitro and in vivo experiments were performed to evaluate the role of CDK1 in ACC progression through gain and loss of function assays in ACC cells. CDK1 inhibitors were screened to identify potential candidates for the treatment of ACC. RNA sequencing, co-immunoprecipitation, and immunofluorescence assays were used to elucidate the mechanism. Results Overexpression of CDK1 in ACC cell lines promoted proliferation and induced the epithelial-to-mesenchymal transition (EMT), whereas knockdown of CDK1 expression inhibited growth of ACC cell lines. The CDK1 inhibitor, cucurbitacin E (CurE), had the best inhibitory effect with good time-and dose-dependent activity both in vitro and in vivo. CurE had a greater inhibitory effect on ACC xenografts in nude mice than mitotane, without obvious adverse effects. Most importantly, combined treatment with CurE and mitotane almost totally eliminated ACC tumors. With respect to mechanism, CDK1 facilitated the EMT of ACC cells via Slug and Twist and locked ACC cells into the G2/M checkpoint through interaction with UBE2C and AURKA/B. CDK1 also regulated pyroptosis, apoptosis, and necroptosis (PANoptosis) of ACC cells through binding with the PANoptosome in a ZBP1-dependent way. Conclusions CDK1 could be exploited as an essential therapeutic target of ACC via regulating the EMT, the G2/M checkpoint, and PANoptosis. Thus, CurE may be a potential candidate drug for ACC therapy with good safety and efficacy, which will meet the great need of patients with ACC.
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allfields	10.1186/s12967-022-03641-y doi (DE-627)SPR051031876 (SPR)s12967-022-03641-y-e DE-627 ger DE-627 rakwb eng Ren, Liwen verfasserin aut CDK1 serves as a therapeutic target of adrenocortical carcinoma via regulating epithelial–mesenchymal transition, G2/M phase transition, and PANoptosis 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2022 Background Adrenocortical carcinoma (ACC) is an extremely rare, aggressive tumor with few effective therapeutic options or drugs. Mitotane (Mtn), which is the only authorized therapeutic drug, came out in 1970 and is still the only first-line treatment for ACC in spite of serious adverse reaction and a high recurrence rate. Methods By in silico analysis of the ACC dataset in the cancer genome atlas (TCGA), we determined that high expression levels of cyclin-dependent kinase-1 (CDK1) were significantly related to the adverse clinical outcomes of ACC. In vitro and in vivo experiments were performed to evaluate the role of CDK1 in ACC progression through gain and loss of function assays in ACC cells. CDK1 inhibitors were screened to identify potential candidates for the treatment of ACC. RNA sequencing, co-immunoprecipitation, and immunofluorescence assays were used to elucidate the mechanism. Results Overexpression of CDK1 in ACC cell lines promoted proliferation and induced the epithelial-to-mesenchymal transition (EMT), whereas knockdown of CDK1 expression inhibited growth of ACC cell lines. The CDK1 inhibitor, cucurbitacin E (CurE), had the best inhibitory effect with good time-and dose-dependent activity both in vitro and in vivo. CurE had a greater inhibitory effect on ACC xenografts in nude mice than mitotane, without obvious adverse effects. Most importantly, combined treatment with CurE and mitotane almost totally eliminated ACC tumors. With respect to mechanism, CDK1 facilitated the EMT of ACC cells via Slug and Twist and locked ACC cells into the G2/M checkpoint through interaction with UBE2C and AURKA/B. CDK1 also regulated pyroptosis, apoptosis, and necroptosis (PANoptosis) of ACC cells through binding with the PANoptosome in a ZBP1-dependent way. Conclusions CDK1 could be exploited as an essential therapeutic target of ACC via regulating the EMT, the G2/M checkpoint, and PANoptosis. Thus, CurE may be a potential candidate drug for ACC therapy with good safety and efficacy, which will meet the great need of patients with ACC. Adrenocortical carcinoma (dpeaa)DE-He213 CDK1 (dpeaa)DE-He213 Cucurbitacin E (dpeaa)DE-He213 Mitotane (dpeaa)DE-He213 EMT (dpeaa)DE-He213 Epithelial-mesenchymal transition (dpeaa)DE-He213 PANoptosis (dpeaa)DE-He213 Yang, Yihui aut Li, Wan aut Zheng, Xiangjin aut Liu, Jinyi aut Li, Sha aut Yang, Hong aut Zhang, Yizhi aut Ge, Binbin aut Zhang, Sen aut Fu, Weiqi aut Dong, Dexin aut Du, Guanhua aut Wang, Jinhua (orcid)0000-0001-8367-0787 aut Enthalten in Journal of translational medicine London : BioMed Central, 2003 20(2022), 1 vom: 02. Okt. (DE-627)369084136 (DE-600)2118570-0 1479-5876 nnns volume:20 year:2022 number:1 day:02 month:10 https://dx.doi.org/10.1186/s12967-022-03641-y 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_31 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 20 2022 1 02 10
spelling	10.1186/s12967-022-03641-y doi (DE-627)SPR051031876 (SPR)s12967-022-03641-y-e DE-627 ger DE-627 rakwb eng Ren, Liwen verfasserin aut CDK1 serves as a therapeutic target of adrenocortical carcinoma via regulating epithelial–mesenchymal transition, G2/M phase transition, and PANoptosis 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2022 Background Adrenocortical carcinoma (ACC) is an extremely rare, aggressive tumor with few effective therapeutic options or drugs. Mitotane (Mtn), which is the only authorized therapeutic drug, came out in 1970 and is still the only first-line treatment for ACC in spite of serious adverse reaction and a high recurrence rate. Methods By in silico analysis of the ACC dataset in the cancer genome atlas (TCGA), we determined that high expression levels of cyclin-dependent kinase-1 (CDK1) were significantly related to the adverse clinical outcomes of ACC. In vitro and in vivo experiments were performed to evaluate the role of CDK1 in ACC progression through gain and loss of function assays in ACC cells. CDK1 inhibitors were screened to identify potential candidates for the treatment of ACC. RNA sequencing, co-immunoprecipitation, and immunofluorescence assays were used to elucidate the mechanism. Results Overexpression of CDK1 in ACC cell lines promoted proliferation and induced the epithelial-to-mesenchymal transition (EMT), whereas knockdown of CDK1 expression inhibited growth of ACC cell lines. The CDK1 inhibitor, cucurbitacin E (CurE), had the best inhibitory effect with good time-and dose-dependent activity both in vitro and in vivo. CurE had a greater inhibitory effect on ACC xenografts in nude mice than mitotane, without obvious adverse effects. Most importantly, combined treatment with CurE and mitotane almost totally eliminated ACC tumors. With respect to mechanism, CDK1 facilitated the EMT of ACC cells via Slug and Twist and locked ACC cells into the G2/M checkpoint through interaction with UBE2C and AURKA/B. CDK1 also regulated pyroptosis, apoptosis, and necroptosis (PANoptosis) of ACC cells through binding with the PANoptosome in a ZBP1-dependent way. Conclusions CDK1 could be exploited as an essential therapeutic target of ACC via regulating the EMT, the G2/M checkpoint, and PANoptosis. Thus, CurE may be a potential candidate drug for ACC therapy with good safety and efficacy, which will meet the great need of patients with ACC. Adrenocortical carcinoma (dpeaa)DE-He213 CDK1 (dpeaa)DE-He213 Cucurbitacin E (dpeaa)DE-He213 Mitotane (dpeaa)DE-He213 EMT (dpeaa)DE-He213 Epithelial-mesenchymal transition (dpeaa)DE-He213 PANoptosis (dpeaa)DE-He213 Yang, Yihui aut Li, Wan aut Zheng, Xiangjin aut Liu, Jinyi aut Li, Sha aut Yang, Hong aut Zhang, Yizhi aut Ge, Binbin aut Zhang, Sen aut Fu, Weiqi aut Dong, Dexin aut Du, Guanhua aut Wang, Jinhua (orcid)0000-0001-8367-0787 aut Enthalten in Journal of translational medicine London : BioMed Central, 2003 20(2022), 1 vom: 02. Okt. (DE-627)369084136 (DE-600)2118570-0 1479-5876 nnns volume:20 year:2022 number:1 day:02 month:10 https://dx.doi.org/10.1186/s12967-022-03641-y 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_31 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 20 2022 1 02 10
allfields_unstemmed	10.1186/s12967-022-03641-y doi (DE-627)SPR051031876 (SPR)s12967-022-03641-y-e DE-627 ger DE-627 rakwb eng Ren, Liwen verfasserin aut CDK1 serves as a therapeutic target of adrenocortical carcinoma via regulating epithelial–mesenchymal transition, G2/M phase transition, and PANoptosis 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2022 Background Adrenocortical carcinoma (ACC) is an extremely rare, aggressive tumor with few effective therapeutic options or drugs. Mitotane (Mtn), which is the only authorized therapeutic drug, came out in 1970 and is still the only first-line treatment for ACC in spite of serious adverse reaction and a high recurrence rate. Methods By in silico analysis of the ACC dataset in the cancer genome atlas (TCGA), we determined that high expression levels of cyclin-dependent kinase-1 (CDK1) were significantly related to the adverse clinical outcomes of ACC. In vitro and in vivo experiments were performed to evaluate the role of CDK1 in ACC progression through gain and loss of function assays in ACC cells. CDK1 inhibitors were screened to identify potential candidates for the treatment of ACC. RNA sequencing, co-immunoprecipitation, and immunofluorescence assays were used to elucidate the mechanism. Results Overexpression of CDK1 in ACC cell lines promoted proliferation and induced the epithelial-to-mesenchymal transition (EMT), whereas knockdown of CDK1 expression inhibited growth of ACC cell lines. The CDK1 inhibitor, cucurbitacin E (CurE), had the best inhibitory effect with good time-and dose-dependent activity both in vitro and in vivo. CurE had a greater inhibitory effect on ACC xenografts in nude mice than mitotane, without obvious adverse effects. Most importantly, combined treatment with CurE and mitotane almost totally eliminated ACC tumors. With respect to mechanism, CDK1 facilitated the EMT of ACC cells via Slug and Twist and locked ACC cells into the G2/M checkpoint through interaction with UBE2C and AURKA/B. CDK1 also regulated pyroptosis, apoptosis, and necroptosis (PANoptosis) of ACC cells through binding with the PANoptosome in a ZBP1-dependent way. Conclusions CDK1 could be exploited as an essential therapeutic target of ACC via regulating the EMT, the G2/M checkpoint, and PANoptosis. Thus, CurE may be a potential candidate drug for ACC therapy with good safety and efficacy, which will meet the great need of patients with ACC. Adrenocortical carcinoma (dpeaa)DE-He213 CDK1 (dpeaa)DE-He213 Cucurbitacin E (dpeaa)DE-He213 Mitotane (dpeaa)DE-He213 EMT (dpeaa)DE-He213 Epithelial-mesenchymal transition (dpeaa)DE-He213 PANoptosis (dpeaa)DE-He213 Yang, Yihui aut Li, Wan aut Zheng, Xiangjin aut Liu, Jinyi aut Li, Sha aut Yang, Hong aut Zhang, Yizhi aut Ge, Binbin aut Zhang, Sen aut Fu, Weiqi aut Dong, Dexin aut Du, Guanhua aut Wang, Jinhua (orcid)0000-0001-8367-0787 aut Enthalten in Journal of translational medicine London : BioMed Central, 2003 20(2022), 1 vom: 02. Okt. (DE-627)369084136 (DE-600)2118570-0 1479-5876 nnns volume:20 year:2022 number:1 day:02 month:10 https://dx.doi.org/10.1186/s12967-022-03641-y 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_31 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 20 2022 1 02 10
allfieldsGer	10.1186/s12967-022-03641-y doi (DE-627)SPR051031876 (SPR)s12967-022-03641-y-e DE-627 ger DE-627 rakwb eng Ren, Liwen verfasserin aut CDK1 serves as a therapeutic target of adrenocortical carcinoma via regulating epithelial–mesenchymal transition, G2/M phase transition, and PANoptosis 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2022 Background Adrenocortical carcinoma (ACC) is an extremely rare, aggressive tumor with few effective therapeutic options or drugs. Mitotane (Mtn), which is the only authorized therapeutic drug, came out in 1970 and is still the only first-line treatment for ACC in spite of serious adverse reaction and a high recurrence rate. Methods By in silico analysis of the ACC dataset in the cancer genome atlas (TCGA), we determined that high expression levels of cyclin-dependent kinase-1 (CDK1) were significantly related to the adverse clinical outcomes of ACC. In vitro and in vivo experiments were performed to evaluate the role of CDK1 in ACC progression through gain and loss of function assays in ACC cells. CDK1 inhibitors were screened to identify potential candidates for the treatment of ACC. RNA sequencing, co-immunoprecipitation, and immunofluorescence assays were used to elucidate the mechanism. Results Overexpression of CDK1 in ACC cell lines promoted proliferation and induced the epithelial-to-mesenchymal transition (EMT), whereas knockdown of CDK1 expression inhibited growth of ACC cell lines. The CDK1 inhibitor, cucurbitacin E (CurE), had the best inhibitory effect with good time-and dose-dependent activity both in vitro and in vivo. CurE had a greater inhibitory effect on ACC xenografts in nude mice than mitotane, without obvious adverse effects. Most importantly, combined treatment with CurE and mitotane almost totally eliminated ACC tumors. With respect to mechanism, CDK1 facilitated the EMT of ACC cells via Slug and Twist and locked ACC cells into the G2/M checkpoint through interaction with UBE2C and AURKA/B. CDK1 also regulated pyroptosis, apoptosis, and necroptosis (PANoptosis) of ACC cells through binding with the PANoptosome in a ZBP1-dependent way. Conclusions CDK1 could be exploited as an essential therapeutic target of ACC via regulating the EMT, the G2/M checkpoint, and PANoptosis. Thus, CurE may be a potential candidate drug for ACC therapy with good safety and efficacy, which will meet the great need of patients with ACC. Adrenocortical carcinoma (dpeaa)DE-He213 CDK1 (dpeaa)DE-He213 Cucurbitacin E (dpeaa)DE-He213 Mitotane (dpeaa)DE-He213 EMT (dpeaa)DE-He213 Epithelial-mesenchymal transition (dpeaa)DE-He213 PANoptosis (dpeaa)DE-He213 Yang, Yihui aut Li, Wan aut Zheng, Xiangjin aut Liu, Jinyi aut Li, Sha aut Yang, Hong aut Zhang, Yizhi aut Ge, Binbin aut Zhang, Sen aut Fu, Weiqi aut Dong, Dexin aut Du, Guanhua aut Wang, Jinhua (orcid)0000-0001-8367-0787 aut Enthalten in Journal of translational medicine London : BioMed Central, 2003 20(2022), 1 vom: 02. Okt. (DE-627)369084136 (DE-600)2118570-0 1479-5876 nnns volume:20 year:2022 number:1 day:02 month:10 https://dx.doi.org/10.1186/s12967-022-03641-y 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_31 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 20 2022 1 02 10
allfieldsSound	10.1186/s12967-022-03641-y doi (DE-627)SPR051031876 (SPR)s12967-022-03641-y-e DE-627 ger DE-627 rakwb eng Ren, Liwen verfasserin aut CDK1 serves as a therapeutic target of adrenocortical carcinoma via regulating epithelial–mesenchymal transition, G2/M phase transition, and PANoptosis 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2022 Background Adrenocortical carcinoma (ACC) is an extremely rare, aggressive tumor with few effective therapeutic options or drugs. Mitotane (Mtn), which is the only authorized therapeutic drug, came out in 1970 and is still the only first-line treatment for ACC in spite of serious adverse reaction and a high recurrence rate. Methods By in silico analysis of the ACC dataset in the cancer genome atlas (TCGA), we determined that high expression levels of cyclin-dependent kinase-1 (CDK1) were significantly related to the adverse clinical outcomes of ACC. In vitro and in vivo experiments were performed to evaluate the role of CDK1 in ACC progression through gain and loss of function assays in ACC cells. CDK1 inhibitors were screened to identify potential candidates for the treatment of ACC. RNA sequencing, co-immunoprecipitation, and immunofluorescence assays were used to elucidate the mechanism. Results Overexpression of CDK1 in ACC cell lines promoted proliferation and induced the epithelial-to-mesenchymal transition (EMT), whereas knockdown of CDK1 expression inhibited growth of ACC cell lines. The CDK1 inhibitor, cucurbitacin E (CurE), had the best inhibitory effect with good time-and dose-dependent activity both in vitro and in vivo. CurE had a greater inhibitory effect on ACC xenografts in nude mice than mitotane, without obvious adverse effects. Most importantly, combined treatment with CurE and mitotane almost totally eliminated ACC tumors. With respect to mechanism, CDK1 facilitated the EMT of ACC cells via Slug and Twist and locked ACC cells into the G2/M checkpoint through interaction with UBE2C and AURKA/B. CDK1 also regulated pyroptosis, apoptosis, and necroptosis (PANoptosis) of ACC cells through binding with the PANoptosome in a ZBP1-dependent way. Conclusions CDK1 could be exploited as an essential therapeutic target of ACC via regulating the EMT, the G2/M checkpoint, and PANoptosis. Thus, CurE may be a potential candidate drug for ACC therapy with good safety and efficacy, which will meet the great need of patients with ACC. Adrenocortical carcinoma (dpeaa)DE-He213 CDK1 (dpeaa)DE-He213 Cucurbitacin E (dpeaa)DE-He213 Mitotane (dpeaa)DE-He213 EMT (dpeaa)DE-He213 Epithelial-mesenchymal transition (dpeaa)DE-He213 PANoptosis (dpeaa)DE-He213 Yang, Yihui aut Li, Wan aut Zheng, Xiangjin aut Liu, Jinyi aut Li, Sha aut Yang, Hong aut Zhang, Yizhi aut Ge, Binbin aut Zhang, Sen aut Fu, Weiqi aut Dong, Dexin aut Du, Guanhua aut Wang, Jinhua (orcid)0000-0001-8367-0787 aut Enthalten in Journal of translational medicine London : BioMed Central, 2003 20(2022), 1 vom: 02. Okt. (DE-627)369084136 (DE-600)2118570-0 1479-5876 nnns volume:20 year:2022 number:1 day:02 month:10 https://dx.doi.org/10.1186/s12967-022-03641-y 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_31 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 20 2022 1 02 10
language	English
source	Enthalten in Journal of translational medicine 20(2022), 1 vom: 02. Okt. volume:20 year:2022 number:1 day:02 month:10
sourceStr	Enthalten in Journal of translational medicine 20(2022), 1 vom: 02. Okt. volume:20 year:2022 number:1 day:02 month:10
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	Adrenocortical carcinoma CDK1 Cucurbitacin E Mitotane EMT Epithelial-mesenchymal transition PANoptosis
isfreeaccess_bool	true
container_title	Journal of translational medicine
authorswithroles_txt_mv	Ren, Liwen @@aut@@ Yang, Yihui @@aut@@ Li, Wan @@aut@@ Zheng, Xiangjin @@aut@@ Liu, Jinyi @@aut@@ Li, Sha @@aut@@ Yang, Hong @@aut@@ Zhang, Yizhi @@aut@@ Ge, Binbin @@aut@@ Zhang, Sen @@aut@@ Fu, Weiqi @@aut@@ Dong, Dexin @@aut@@ Du, Guanhua @@aut@@ Wang, Jinhua @@aut@@
publishDateDaySort_date	2022-10-02T00:00:00Z
hierarchy_top_id	369084136
id	SPR051031876
language_de	englisch
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Mitotane (Mtn), which is the only authorized therapeutic drug, came out in 1970 and is still the only first-line treatment for ACC in spite of serious adverse reaction and a high recurrence rate. Methods By in silico analysis of the ACC dataset in the cancer genome atlas (TCGA), we determined that high expression levels of cyclin-dependent kinase-1 (CDK1) were significantly related to the adverse clinical outcomes of ACC. In vitro and in vivo experiments were performed to evaluate the role of CDK1 in ACC progression through gain and loss of function assays in ACC cells. CDK1 inhibitors were screened to identify potential candidates for the treatment of ACC. RNA sequencing, co-immunoprecipitation, and immunofluorescence assays were used to elucidate the mechanism. Results Overexpression of CDK1 in ACC cell lines promoted proliferation and induced the epithelial-to-mesenchymal transition (EMT), whereas knockdown of CDK1 expression inhibited growth of ACC cell lines. The CDK1 inhibitor, cucurbitacin E (CurE), had the best inhibitory effect with good time-and dose-dependent activity both in vitro and in vivo. CurE had a greater inhibitory effect on ACC xenografts in nude mice than mitotane, without obvious adverse effects. Most importantly, combined treatment with CurE and mitotane almost totally eliminated ACC tumors. With respect to mechanism, CDK1 facilitated the EMT of ACC cells via Slug and Twist and locked ACC cells into the G2/M checkpoint through interaction with UBE2C and AURKA/B. CDK1 also regulated pyroptosis, apoptosis, and necroptosis (PANoptosis) of ACC cells through binding with the PANoptosome in a ZBP1-dependent way. Conclusions CDK1 could be exploited as an essential therapeutic target of ACC via regulating the EMT, the G2/M checkpoint, and PANoptosis. 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author	Ren, Liwen
spellingShingle	Ren, Liwen misc Adrenocortical carcinoma misc CDK1 misc Cucurbitacin E misc Mitotane misc EMT misc Epithelial-mesenchymal transition misc PANoptosis CDK1 serves as a therapeutic target of adrenocortical carcinoma via regulating epithelial–mesenchymal transition, G2/M phase transition, and PANoptosis
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topic_title	CDK1 serves as a therapeutic target of adrenocortical carcinoma via regulating epithelial–mesenchymal transition, G2/M phase transition, and PANoptosis Adrenocortical carcinoma (dpeaa)DE-He213 CDK1 (dpeaa)DE-He213 Cucurbitacin E (dpeaa)DE-He213 Mitotane (dpeaa)DE-He213 EMT (dpeaa)DE-He213 Epithelial-mesenchymal transition (dpeaa)DE-He213 PANoptosis (dpeaa)DE-He213
topic	misc Adrenocortical carcinoma misc CDK1 misc Cucurbitacin E misc Mitotane misc EMT misc Epithelial-mesenchymal transition misc PANoptosis
topic_unstemmed	misc Adrenocortical carcinoma misc CDK1 misc Cucurbitacin E misc Mitotane misc EMT misc Epithelial-mesenchymal transition misc PANoptosis
topic_browse	misc Adrenocortical carcinoma misc CDK1 misc Cucurbitacin E misc Mitotane misc EMT misc Epithelial-mesenchymal transition misc PANoptosis
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title	CDK1 serves as a therapeutic target of adrenocortical carcinoma via regulating epithelial–mesenchymal transition, G2/M phase transition, and PANoptosis
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title_full	CDK1 serves as a therapeutic target of adrenocortical carcinoma via regulating epithelial–mesenchymal transition, G2/M phase transition, and PANoptosis
author_sort	Ren, Liwen
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author_browse	Ren, Liwen Yang, Yihui Li, Wan Zheng, Xiangjin Liu, Jinyi Li, Sha Yang, Hong Zhang, Yizhi Ge, Binbin Zhang, Sen Fu, Weiqi Dong, Dexin Du, Guanhua Wang, Jinhua
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author-letter	Ren, Liwen
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title_sort	cdk1 serves as a therapeutic target of adrenocortical carcinoma via regulating epithelial–mesenchymal transition, g2/m phase transition, and panoptosis
title_auth	CDK1 serves as a therapeutic target of adrenocortical carcinoma via regulating epithelial–mesenchymal transition, G2/M phase transition, and PANoptosis
abstract	Background Adrenocortical carcinoma (ACC) is an extremely rare, aggressive tumor with few effective therapeutic options or drugs. Mitotane (Mtn), which is the only authorized therapeutic drug, came out in 1970 and is still the only first-line treatment for ACC in spite of serious adverse reaction and a high recurrence rate. Methods By in silico analysis of the ACC dataset in the cancer genome atlas (TCGA), we determined that high expression levels of cyclin-dependent kinase-1 (CDK1) were significantly related to the adverse clinical outcomes of ACC. In vitro and in vivo experiments were performed to evaluate the role of CDK1 in ACC progression through gain and loss of function assays in ACC cells. CDK1 inhibitors were screened to identify potential candidates for the treatment of ACC. RNA sequencing, co-immunoprecipitation, and immunofluorescence assays were used to elucidate the mechanism. Results Overexpression of CDK1 in ACC cell lines promoted proliferation and induced the epithelial-to-mesenchymal transition (EMT), whereas knockdown of CDK1 expression inhibited growth of ACC cell lines. The CDK1 inhibitor, cucurbitacin E (CurE), had the best inhibitory effect with good time-and dose-dependent activity both in vitro and in vivo. CurE had a greater inhibitory effect on ACC xenografts in nude mice than mitotane, without obvious adverse effects. Most importantly, combined treatment with CurE and mitotane almost totally eliminated ACC tumors. With respect to mechanism, CDK1 facilitated the EMT of ACC cells via Slug and Twist and locked ACC cells into the G2/M checkpoint through interaction with UBE2C and AURKA/B. CDK1 also regulated pyroptosis, apoptosis, and necroptosis (PANoptosis) of ACC cells through binding with the PANoptosome in a ZBP1-dependent way. Conclusions CDK1 could be exploited as an essential therapeutic target of ACC via regulating the EMT, the G2/M checkpoint, and PANoptosis. Thus, CurE may be a potential candidate drug for ACC therapy with good safety and efficacy, which will meet the great need of patients with ACC. © The Author(s) 2022
abstractGer	Background Adrenocortical carcinoma (ACC) is an extremely rare, aggressive tumor with few effective therapeutic options or drugs. Mitotane (Mtn), which is the only authorized therapeutic drug, came out in 1970 and is still the only first-line treatment for ACC in spite of serious adverse reaction and a high recurrence rate. Methods By in silico analysis of the ACC dataset in the cancer genome atlas (TCGA), we determined that high expression levels of cyclin-dependent kinase-1 (CDK1) were significantly related to the adverse clinical outcomes of ACC. In vitro and in vivo experiments were performed to evaluate the role of CDK1 in ACC progression through gain and loss of function assays in ACC cells. CDK1 inhibitors were screened to identify potential candidates for the treatment of ACC. RNA sequencing, co-immunoprecipitation, and immunofluorescence assays were used to elucidate the mechanism. Results Overexpression of CDK1 in ACC cell lines promoted proliferation and induced the epithelial-to-mesenchymal transition (EMT), whereas knockdown of CDK1 expression inhibited growth of ACC cell lines. The CDK1 inhibitor, cucurbitacin E (CurE), had the best inhibitory effect with good time-and dose-dependent activity both in vitro and in vivo. CurE had a greater inhibitory effect on ACC xenografts in nude mice than mitotane, without obvious adverse effects. Most importantly, combined treatment with CurE and mitotane almost totally eliminated ACC tumors. With respect to mechanism, CDK1 facilitated the EMT of ACC cells via Slug and Twist and locked ACC cells into the G2/M checkpoint through interaction with UBE2C and AURKA/B. CDK1 also regulated pyroptosis, apoptosis, and necroptosis (PANoptosis) of ACC cells through binding with the PANoptosome in a ZBP1-dependent way. Conclusions CDK1 could be exploited as an essential therapeutic target of ACC via regulating the EMT, the G2/M checkpoint, and PANoptosis. Thus, CurE may be a potential candidate drug for ACC therapy with good safety and efficacy, which will meet the great need of patients with ACC. © The Author(s) 2022
abstract_unstemmed	Background Adrenocortical carcinoma (ACC) is an extremely rare, aggressive tumor with few effective therapeutic options or drugs. Mitotane (Mtn), which is the only authorized therapeutic drug, came out in 1970 and is still the only first-line treatment for ACC in spite of serious adverse reaction and a high recurrence rate. Methods By in silico analysis of the ACC dataset in the cancer genome atlas (TCGA), we determined that high expression levels of cyclin-dependent kinase-1 (CDK1) were significantly related to the adverse clinical outcomes of ACC. In vitro and in vivo experiments were performed to evaluate the role of CDK1 in ACC progression through gain and loss of function assays in ACC cells. CDK1 inhibitors were screened to identify potential candidates for the treatment of ACC. RNA sequencing, co-immunoprecipitation, and immunofluorescence assays were used to elucidate the mechanism. Results Overexpression of CDK1 in ACC cell lines promoted proliferation and induced the epithelial-to-mesenchymal transition (EMT), whereas knockdown of CDK1 expression inhibited growth of ACC cell lines. The CDK1 inhibitor, cucurbitacin E (CurE), had the best inhibitory effect with good time-and dose-dependent activity both in vitro and in vivo. CurE had a greater inhibitory effect on ACC xenografts in nude mice than mitotane, without obvious adverse effects. Most importantly, combined treatment with CurE and mitotane almost totally eliminated ACC tumors. With respect to mechanism, CDK1 facilitated the EMT of ACC cells via Slug and Twist and locked ACC cells into the G2/M checkpoint through interaction with UBE2C and AURKA/B. CDK1 also regulated pyroptosis, apoptosis, and necroptosis (PANoptosis) of ACC cells through binding with the PANoptosome in a ZBP1-dependent way. Conclusions CDK1 could be exploited as an essential therapeutic target of ACC via regulating the EMT, the G2/M checkpoint, and PANoptosis. Thus, CurE may be a potential candidate drug for ACC therapy with good safety and efficacy, which will meet the great need of patients with ACC. © The Author(s) 2022
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title_short	CDK1 serves as a therapeutic target of adrenocortical carcinoma via regulating epithelial–mesenchymal transition, G2/M phase transition, and PANoptosis
url	https://dx.doi.org/10.1186/s12967-022-03641-y
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author2	Yang, Yihui Li, Wan Zheng, Xiangjin Liu, Jinyi Li, Sha Yang, Hong Zhang, Yizhi Ge, Binbin Zhang, Sen Fu, Weiqi Dong, Dexin Du, Guanhua Wang, Jinhua
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CDK1 serves as a therapeutic target of adrenocortical carcinoma via regulating epithelial–mesenchymal transition, G2/M phase transition, and PANoptosis

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