Dihydroartemisinin-induced unfolded protein response feedback attenuates ferroptosis via PERK/ATF4/HSPA5 pathway in glioma cells

Abstract Background Dihydroartemisinin (DHA) has been shown to exert anticancer activity through iron-dependent reactive oxygen species (ROS) generation, which is similar to ferroptosis, a novel form of cell death. However, whether DHA causes ferroptosis in glioma cells and the potential regulatory...
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Autor*in:	Yibing Chen [verfasserIn] Yanjun Mi [verfasserIn] Xiaofei Zhang [verfasserIn] Qian Ma [verfasserIn] Yucen Song [verfasserIn] Liwei Zhang [verfasserIn] Dandan Wang [verfasserIn] Jinliang Xing [verfasserIn] Benxin Hou [verfasserIn] Haolong Li [verfasserIn] Huan Jin [verfasserIn] Wei Du [verfasserIn] Zhengzhi Zou [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2019

Schlagwörter:	Dihydroartemisinin Ferroptosis GPX4 Endoplasmic reticulum stress HSPA5 Glioma

Übergeordnetes Werk:	In: Journal of Experimental & Clinical Cancer Research - BMC, 2008, 38(2019), 1, Seite 16
Übergeordnetes Werk:	volume:38 ; year:2019 ; number:1 ; pages:16

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.1186/s13046-019-1413-7

Katalog-ID:	DOAJ07647058X

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520			\|a Abstract Background Dihydroartemisinin (DHA) has been shown to exert anticancer activity through iron-dependent reactive oxygen species (ROS) generation, which is similar to ferroptosis, a novel form of cell death. However, whether DHA causes ferroptosis in glioma cells and the potential regulatory mechanisms remain unclear. Methods Effects of DHA on the proliferation, cell death, ROS and lipid ROS generation as well as reduced gluthione consumption were assessed in glioma cells with or without ferroptosis inhibitor. The biological mechanisms by which glioma cells attenuate the pro-ferroptotic effects of DHA were assessed using molecular methods. Results DHA induced ferroptosis in glioma cells, as characterized by iron-dependent cell death accompanied with ROS generation and lipid peroxidation. However, DHA treatment simultaneously activated a feedback pathway of ferroptosis by increasing the expression of heat shock protein family A (Hsp70) member 5 (HSPA5). Mechanistically, DHA caused endoplasmic reticulum (ER) stress in glioma cells, which resulted in the induction of HSPA5 expression by protein kinase R-like ER kinase (PERK)-upregulated activating transcription factor 4 (ATF4). Subsequent HSPA5 upregulation increased the expression and activity of glutathione peroxidase 4 (GPX4), which neutralized DHA-induced lipid peroxidation and thus protected glioma cells from ferroptosis. Inhibition of the PERK-ATF4-HSPA5-GPX4 pathway using siRNA or small molecules increased DHA sensitivity of glioma cells by increasing ferroptosis both in vitro and in vivo. Conclusions Collectively, these data suggested that ferroptosis might be a novel anticancer mechanism of DHA in glioma and HSPA5 may serve as a negative regulator of DHA-induced ferroptosis. Therefore, inhibiting the negative feedback pathway would be a promising therapeutic strategy to strengthen the anti-glioma activity of DHA.
650		4	\|a Dihydroartemisinin
650		4	\|a Ferroptosis
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650		4	\|a Endoplasmic reticulum stress
650		4	\|a HSPA5
650		4	\|a Glioma
653		0	\|a Neoplasms. Tumors. Oncology. Including cancer and carcinogens
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700	0		\|a Haolong Li \|e verfasserin \|4 aut
700	0		\|a Huan Jin \|e verfasserin \|4 aut
700	0		\|a Wei Du \|e verfasserin \|4 aut
700	0		\|a Zhengzhi Zou \|e verfasserin \|4 aut
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allfields	10.1186/s13046-019-1413-7 doi (DE-627)DOAJ07647058X (DE-599)DOAJ018c6c9bb2b44898bcbd00bd3481b804 DE-627 ger DE-627 rakwb eng RC254-282 Yibing Chen verfasserin aut Dihydroartemisinin-induced unfolded protein response feedback attenuates ferroptosis via PERK/ATF4/HSPA5 pathway in glioma cells 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Background Dihydroartemisinin (DHA) has been shown to exert anticancer activity through iron-dependent reactive oxygen species (ROS) generation, which is similar to ferroptosis, a novel form of cell death. However, whether DHA causes ferroptosis in glioma cells and the potential regulatory mechanisms remain unclear. Methods Effects of DHA on the proliferation, cell death, ROS and lipid ROS generation as well as reduced gluthione consumption were assessed in glioma cells with or without ferroptosis inhibitor. The biological mechanisms by which glioma cells attenuate the pro-ferroptotic effects of DHA were assessed using molecular methods. Results DHA induced ferroptosis in glioma cells, as characterized by iron-dependent cell death accompanied with ROS generation and lipid peroxidation. However, DHA treatment simultaneously activated a feedback pathway of ferroptosis by increasing the expression of heat shock protein family A (Hsp70) member 5 (HSPA5). Mechanistically, DHA caused endoplasmic reticulum (ER) stress in glioma cells, which resulted in the induction of HSPA5 expression by protein kinase R-like ER kinase (PERK)-upregulated activating transcription factor 4 (ATF4). Subsequent HSPA5 upregulation increased the expression and activity of glutathione peroxidase 4 (GPX4), which neutralized DHA-induced lipid peroxidation and thus protected glioma cells from ferroptosis. Inhibition of the PERK-ATF4-HSPA5-GPX4 pathway using siRNA or small molecules increased DHA sensitivity of glioma cells by increasing ferroptosis both in vitro and in vivo. Conclusions Collectively, these data suggested that ferroptosis might be a novel anticancer mechanism of DHA in glioma and HSPA5 may serve as a negative regulator of DHA-induced ferroptosis. Therefore, inhibiting the negative feedback pathway would be a promising therapeutic strategy to strengthen the anti-glioma activity of DHA. Dihydroartemisinin Ferroptosis GPX4 Endoplasmic reticulum stress HSPA5 Glioma Neoplasms. Tumors. Oncology. Including cancer and carcinogens Yanjun Mi verfasserin aut Xiaofei Zhang verfasserin aut Qian Ma verfasserin aut Yucen Song verfasserin aut Liwei Zhang verfasserin aut Dandan Wang verfasserin aut Jinliang Xing verfasserin aut Benxin Hou verfasserin aut Haolong Li verfasserin aut Huan Jin verfasserin aut Wei Du verfasserin aut Zhengzhi Zou verfasserin aut In Journal of Experimental & Clinical Cancer Research BMC, 2008 38(2019), 1, Seite 16 (DE-627)568921380 (DE-600)2430698-8 17569966 nnns volume:38 year:2019 number:1 pages:16 https://doi.org/10.1186/s13046-019-1413-7 kostenfrei https://doaj.org/article/018c6c9bb2b44898bcbd00bd3481b804 kostenfrei http://link.springer.com/article/10.1186/s13046-019-1413-7 kostenfrei https://doaj.org/toc/1756-9966 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ 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 38 2019 1 16
spelling	10.1186/s13046-019-1413-7 doi (DE-627)DOAJ07647058X (DE-599)DOAJ018c6c9bb2b44898bcbd00bd3481b804 DE-627 ger DE-627 rakwb eng RC254-282 Yibing Chen verfasserin aut Dihydroartemisinin-induced unfolded protein response feedback attenuates ferroptosis via PERK/ATF4/HSPA5 pathway in glioma cells 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Background Dihydroartemisinin (DHA) has been shown to exert anticancer activity through iron-dependent reactive oxygen species (ROS) generation, which is similar to ferroptosis, a novel form of cell death. However, whether DHA causes ferroptosis in glioma cells and the potential regulatory mechanisms remain unclear. Methods Effects of DHA on the proliferation, cell death, ROS and lipid ROS generation as well as reduced gluthione consumption were assessed in glioma cells with or without ferroptosis inhibitor. The biological mechanisms by which glioma cells attenuate the pro-ferroptotic effects of DHA were assessed using molecular methods. Results DHA induced ferroptosis in glioma cells, as characterized by iron-dependent cell death accompanied with ROS generation and lipid peroxidation. However, DHA treatment simultaneously activated a feedback pathway of ferroptosis by increasing the expression of heat shock protein family A (Hsp70) member 5 (HSPA5). Mechanistically, DHA caused endoplasmic reticulum (ER) stress in glioma cells, which resulted in the induction of HSPA5 expression by protein kinase R-like ER kinase (PERK)-upregulated activating transcription factor 4 (ATF4). Subsequent HSPA5 upregulation increased the expression and activity of glutathione peroxidase 4 (GPX4), which neutralized DHA-induced lipid peroxidation and thus protected glioma cells from ferroptosis. Inhibition of the PERK-ATF4-HSPA5-GPX4 pathway using siRNA or small molecules increased DHA sensitivity of glioma cells by increasing ferroptosis both in vitro and in vivo. Conclusions Collectively, these data suggested that ferroptosis might be a novel anticancer mechanism of DHA in glioma and HSPA5 may serve as a negative regulator of DHA-induced ferroptosis. Therefore, inhibiting the negative feedback pathway would be a promising therapeutic strategy to strengthen the anti-glioma activity of DHA. Dihydroartemisinin Ferroptosis GPX4 Endoplasmic reticulum stress HSPA5 Glioma Neoplasms. Tumors. Oncology. Including cancer and carcinogens Yanjun Mi verfasserin aut Xiaofei Zhang verfasserin aut Qian Ma verfasserin aut Yucen Song verfasserin aut Liwei Zhang verfasserin aut Dandan Wang verfasserin aut Jinliang Xing verfasserin aut Benxin Hou verfasserin aut Haolong Li verfasserin aut Huan Jin verfasserin aut Wei Du verfasserin aut Zhengzhi Zou verfasserin aut In Journal of Experimental & Clinical Cancer Research BMC, 2008 38(2019), 1, Seite 16 (DE-627)568921380 (DE-600)2430698-8 17569966 nnns volume:38 year:2019 number:1 pages:16 https://doi.org/10.1186/s13046-019-1413-7 kostenfrei https://doaj.org/article/018c6c9bb2b44898bcbd00bd3481b804 kostenfrei http://link.springer.com/article/10.1186/s13046-019-1413-7 kostenfrei https://doaj.org/toc/1756-9966 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ 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 38 2019 1 16
allfields_unstemmed	10.1186/s13046-019-1413-7 doi (DE-627)DOAJ07647058X (DE-599)DOAJ018c6c9bb2b44898bcbd00bd3481b804 DE-627 ger DE-627 rakwb eng RC254-282 Yibing Chen verfasserin aut Dihydroartemisinin-induced unfolded protein response feedback attenuates ferroptosis via PERK/ATF4/HSPA5 pathway in glioma cells 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Background Dihydroartemisinin (DHA) has been shown to exert anticancer activity through iron-dependent reactive oxygen species (ROS) generation, which is similar to ferroptosis, a novel form of cell death. However, whether DHA causes ferroptosis in glioma cells and the potential regulatory mechanisms remain unclear. Methods Effects of DHA on the proliferation, cell death, ROS and lipid ROS generation as well as reduced gluthione consumption were assessed in glioma cells with or without ferroptosis inhibitor. The biological mechanisms by which glioma cells attenuate the pro-ferroptotic effects of DHA were assessed using molecular methods. Results DHA induced ferroptosis in glioma cells, as characterized by iron-dependent cell death accompanied with ROS generation and lipid peroxidation. However, DHA treatment simultaneously activated a feedback pathway of ferroptosis by increasing the expression of heat shock protein family A (Hsp70) member 5 (HSPA5). Mechanistically, DHA caused endoplasmic reticulum (ER) stress in glioma cells, which resulted in the induction of HSPA5 expression by protein kinase R-like ER kinase (PERK)-upregulated activating transcription factor 4 (ATF4). Subsequent HSPA5 upregulation increased the expression and activity of glutathione peroxidase 4 (GPX4), which neutralized DHA-induced lipid peroxidation and thus protected glioma cells from ferroptosis. Inhibition of the PERK-ATF4-HSPA5-GPX4 pathway using siRNA or small molecules increased DHA sensitivity of glioma cells by increasing ferroptosis both in vitro and in vivo. Conclusions Collectively, these data suggested that ferroptosis might be a novel anticancer mechanism of DHA in glioma and HSPA5 may serve as a negative regulator of DHA-induced ferroptosis. Therefore, inhibiting the negative feedback pathway would be a promising therapeutic strategy to strengthen the anti-glioma activity of DHA. Dihydroartemisinin Ferroptosis GPX4 Endoplasmic reticulum stress HSPA5 Glioma Neoplasms. Tumors. Oncology. Including cancer and carcinogens Yanjun Mi verfasserin aut Xiaofei Zhang verfasserin aut Qian Ma verfasserin aut Yucen Song verfasserin aut Liwei Zhang verfasserin aut Dandan Wang verfasserin aut Jinliang Xing verfasserin aut Benxin Hou verfasserin aut Haolong Li verfasserin aut Huan Jin verfasserin aut Wei Du verfasserin aut Zhengzhi Zou verfasserin aut In Journal of Experimental & Clinical Cancer Research BMC, 2008 38(2019), 1, Seite 16 (DE-627)568921380 (DE-600)2430698-8 17569966 nnns volume:38 year:2019 number:1 pages:16 https://doi.org/10.1186/s13046-019-1413-7 kostenfrei https://doaj.org/article/018c6c9bb2b44898bcbd00bd3481b804 kostenfrei http://link.springer.com/article/10.1186/s13046-019-1413-7 kostenfrei https://doaj.org/toc/1756-9966 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ 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 38 2019 1 16
allfieldsGer	10.1186/s13046-019-1413-7 doi (DE-627)DOAJ07647058X (DE-599)DOAJ018c6c9bb2b44898bcbd00bd3481b804 DE-627 ger DE-627 rakwb eng RC254-282 Yibing Chen verfasserin aut Dihydroartemisinin-induced unfolded protein response feedback attenuates ferroptosis via PERK/ATF4/HSPA5 pathway in glioma cells 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Background Dihydroartemisinin (DHA) has been shown to exert anticancer activity through iron-dependent reactive oxygen species (ROS) generation, which is similar to ferroptosis, a novel form of cell death. However, whether DHA causes ferroptosis in glioma cells and the potential regulatory mechanisms remain unclear. Methods Effects of DHA on the proliferation, cell death, ROS and lipid ROS generation as well as reduced gluthione consumption were assessed in glioma cells with or without ferroptosis inhibitor. The biological mechanisms by which glioma cells attenuate the pro-ferroptotic effects of DHA were assessed using molecular methods. Results DHA induced ferroptosis in glioma cells, as characterized by iron-dependent cell death accompanied with ROS generation and lipid peroxidation. However, DHA treatment simultaneously activated a feedback pathway of ferroptosis by increasing the expression of heat shock protein family A (Hsp70) member 5 (HSPA5). Mechanistically, DHA caused endoplasmic reticulum (ER) stress in glioma cells, which resulted in the induction of HSPA5 expression by protein kinase R-like ER kinase (PERK)-upregulated activating transcription factor 4 (ATF4). Subsequent HSPA5 upregulation increased the expression and activity of glutathione peroxidase 4 (GPX4), which neutralized DHA-induced lipid peroxidation and thus protected glioma cells from ferroptosis. Inhibition of the PERK-ATF4-HSPA5-GPX4 pathway using siRNA or small molecules increased DHA sensitivity of glioma cells by increasing ferroptosis both in vitro and in vivo. Conclusions Collectively, these data suggested that ferroptosis might be a novel anticancer mechanism of DHA in glioma and HSPA5 may serve as a negative regulator of DHA-induced ferroptosis. Therefore, inhibiting the negative feedback pathway would be a promising therapeutic strategy to strengthen the anti-glioma activity of DHA. Dihydroartemisinin Ferroptosis GPX4 Endoplasmic reticulum stress HSPA5 Glioma Neoplasms. Tumors. Oncology. Including cancer and carcinogens Yanjun Mi verfasserin aut Xiaofei Zhang verfasserin aut Qian Ma verfasserin aut Yucen Song verfasserin aut Liwei Zhang verfasserin aut Dandan Wang verfasserin aut Jinliang Xing verfasserin aut Benxin Hou verfasserin aut Haolong Li verfasserin aut Huan Jin verfasserin aut Wei Du verfasserin aut Zhengzhi Zou verfasserin aut In Journal of Experimental & Clinical Cancer Research BMC, 2008 38(2019), 1, Seite 16 (DE-627)568921380 (DE-600)2430698-8 17569966 nnns volume:38 year:2019 number:1 pages:16 https://doi.org/10.1186/s13046-019-1413-7 kostenfrei https://doaj.org/article/018c6c9bb2b44898bcbd00bd3481b804 kostenfrei http://link.springer.com/article/10.1186/s13046-019-1413-7 kostenfrei https://doaj.org/toc/1756-9966 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ 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 38 2019 1 16
allfieldsSound	10.1186/s13046-019-1413-7 doi (DE-627)DOAJ07647058X (DE-599)DOAJ018c6c9bb2b44898bcbd00bd3481b804 DE-627 ger DE-627 rakwb eng RC254-282 Yibing Chen verfasserin aut Dihydroartemisinin-induced unfolded protein response feedback attenuates ferroptosis via PERK/ATF4/HSPA5 pathway in glioma cells 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Background Dihydroartemisinin (DHA) has been shown to exert anticancer activity through iron-dependent reactive oxygen species (ROS) generation, which is similar to ferroptosis, a novel form of cell death. However, whether DHA causes ferroptosis in glioma cells and the potential regulatory mechanisms remain unclear. Methods Effects of DHA on the proliferation, cell death, ROS and lipid ROS generation as well as reduced gluthione consumption were assessed in glioma cells with or without ferroptosis inhibitor. The biological mechanisms by which glioma cells attenuate the pro-ferroptotic effects of DHA were assessed using molecular methods. Results DHA induced ferroptosis in glioma cells, as characterized by iron-dependent cell death accompanied with ROS generation and lipid peroxidation. However, DHA treatment simultaneously activated a feedback pathway of ferroptosis by increasing the expression of heat shock protein family A (Hsp70) member 5 (HSPA5). Mechanistically, DHA caused endoplasmic reticulum (ER) stress in glioma cells, which resulted in the induction of HSPA5 expression by protein kinase R-like ER kinase (PERK)-upregulated activating transcription factor 4 (ATF4). Subsequent HSPA5 upregulation increased the expression and activity of glutathione peroxidase 4 (GPX4), which neutralized DHA-induced lipid peroxidation and thus protected glioma cells from ferroptosis. Inhibition of the PERK-ATF4-HSPA5-GPX4 pathway using siRNA or small molecules increased DHA sensitivity of glioma cells by increasing ferroptosis both in vitro and in vivo. Conclusions Collectively, these data suggested that ferroptosis might be a novel anticancer mechanism of DHA in glioma and HSPA5 may serve as a negative regulator of DHA-induced ferroptosis. Therefore, inhibiting the negative feedback pathway would be a promising therapeutic strategy to strengthen the anti-glioma activity of DHA. Dihydroartemisinin Ferroptosis GPX4 Endoplasmic reticulum stress HSPA5 Glioma Neoplasms. Tumors. Oncology. Including cancer and carcinogens Yanjun Mi verfasserin aut Xiaofei Zhang verfasserin aut Qian Ma verfasserin aut Yucen Song verfasserin aut Liwei Zhang verfasserin aut Dandan Wang verfasserin aut Jinliang Xing verfasserin aut Benxin Hou verfasserin aut Haolong Li verfasserin aut Huan Jin verfasserin aut Wei Du verfasserin aut Zhengzhi Zou verfasserin aut In Journal of Experimental & Clinical Cancer Research BMC, 2008 38(2019), 1, Seite 16 (DE-627)568921380 (DE-600)2430698-8 17569966 nnns volume:38 year:2019 number:1 pages:16 https://doi.org/10.1186/s13046-019-1413-7 kostenfrei https://doaj.org/article/018c6c9bb2b44898bcbd00bd3481b804 kostenfrei http://link.springer.com/article/10.1186/s13046-019-1413-7 kostenfrei https://doaj.org/toc/1756-9966 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ 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 38 2019 1 16
language	English
source	In Journal of Experimental & Clinical Cancer Research 38(2019), 1, Seite 16 volume:38 year:2019 number:1 pages:16
sourceStr	In Journal of Experimental & Clinical Cancer Research 38(2019), 1, Seite 16 volume:38 year:2019 number:1 pages:16
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	Dihydroartemisinin Ferroptosis GPX4 Endoplasmic reticulum stress HSPA5 Glioma Neoplasms. Tumors. Oncology. Including cancer and carcinogens
isfreeaccess_bool	true
container_title	Journal of Experimental & Clinical Cancer Research
authorswithroles_txt_mv	Yibing Chen @@aut@@ Yanjun Mi @@aut@@ Xiaofei Zhang @@aut@@ Qian Ma @@aut@@ Yucen Song @@aut@@ Liwei Zhang @@aut@@ Dandan Wang @@aut@@ Jinliang Xing @@aut@@ Benxin Hou @@aut@@ Haolong Li @@aut@@ Huan Jin @@aut@@ Wei Du @@aut@@ Zhengzhi Zou @@aut@@
publishDateDaySort_date	2019-01-01T00:00:00Z
hierarchy_top_id	568921380
id	DOAJ07647058X
language_de	englisch
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However, whether DHA causes ferroptosis in glioma cells and the potential regulatory mechanisms remain unclear. Methods Effects of DHA on the proliferation, cell death, ROS and lipid ROS generation as well as reduced gluthione consumption were assessed in glioma cells with or without ferroptosis inhibitor. The biological mechanisms by which glioma cells attenuate the pro-ferroptotic effects of DHA were assessed using molecular methods. Results DHA induced ferroptosis in glioma cells, as characterized by iron-dependent cell death accompanied with ROS generation and lipid peroxidation. However, DHA treatment simultaneously activated a feedback pathway of ferroptosis by increasing the expression of heat shock protein family A (Hsp70) member 5 (HSPA5). Mechanistically, DHA caused endoplasmic reticulum (ER) stress in glioma cells, which resulted in the induction of HSPA5 expression by protein kinase R-like ER kinase (PERK)-upregulated activating transcription factor 4 (ATF4). Subsequent HSPA5 upregulation increased the expression and activity of glutathione peroxidase 4 (GPX4), which neutralized DHA-induced lipid peroxidation and thus protected glioma cells from ferroptosis. Inhibition of the PERK-ATF4-HSPA5-GPX4 pathway using siRNA or small molecules increased DHA sensitivity of glioma cells by increasing ferroptosis both in vitro and in vivo. Conclusions Collectively, these data suggested that ferroptosis might be a novel anticancer mechanism of DHA in glioma and HSPA5 may serve as a negative regulator of DHA-induced ferroptosis. 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callnumber-first	R - Medicine
author	Yibing Chen
spellingShingle	Yibing Chen misc RC254-282 misc Dihydroartemisinin misc Ferroptosis misc GPX4 misc Endoplasmic reticulum stress misc HSPA5 misc Glioma misc Neoplasms. Tumors. Oncology. Including cancer and carcinogens Dihydroartemisinin-induced unfolded protein response feedback attenuates ferroptosis via PERK/ATF4/HSPA5 pathway in glioma cells
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topic_title	RC254-282 Dihydroartemisinin-induced unfolded protein response feedback attenuates ferroptosis via PERK/ATF4/HSPA5 pathway in glioma cells Dihydroartemisinin Ferroptosis GPX4 Endoplasmic reticulum stress HSPA5 Glioma
topic	misc RC254-282 misc Dihydroartemisinin misc Ferroptosis misc GPX4 misc Endoplasmic reticulum stress misc HSPA5 misc Glioma misc Neoplasms. Tumors. Oncology. Including cancer and carcinogens
topic_unstemmed	misc RC254-282 misc Dihydroartemisinin misc Ferroptosis misc GPX4 misc Endoplasmic reticulum stress misc HSPA5 misc Glioma misc Neoplasms. Tumors. Oncology. Including cancer and carcinogens
topic_browse	misc RC254-282 misc Dihydroartemisinin misc Ferroptosis misc GPX4 misc Endoplasmic reticulum stress misc HSPA5 misc Glioma misc Neoplasms. Tumors. Oncology. Including cancer and carcinogens
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title	Dihydroartemisinin-induced unfolded protein response feedback attenuates ferroptosis via PERK/ATF4/HSPA5 pathway in glioma cells
ctrlnum	(DE-627)DOAJ07647058X (DE-599)DOAJ018c6c9bb2b44898bcbd00bd3481b804
title_full	Dihydroartemisinin-induced unfolded protein response feedback attenuates ferroptosis via PERK/ATF4/HSPA5 pathway in glioma cells
author_sort	Yibing Chen
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author_browse	Yibing Chen Yanjun Mi Xiaofei Zhang Qian Ma Yucen Song Liwei Zhang Dandan Wang Jinliang Xing Benxin Hou Haolong Li Huan Jin Wei Du Zhengzhi Zou
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title_sort	dihydroartemisinin-induced unfolded protein response feedback attenuates ferroptosis via perk/atf4/hspa5 pathway in glioma cells
callnumber	RC254-282
title_auth	Dihydroartemisinin-induced unfolded protein response feedback attenuates ferroptosis via PERK/ATF4/HSPA5 pathway in glioma cells
abstract	Abstract Background Dihydroartemisinin (DHA) has been shown to exert anticancer activity through iron-dependent reactive oxygen species (ROS) generation, which is similar to ferroptosis, a novel form of cell death. However, whether DHA causes ferroptosis in glioma cells and the potential regulatory mechanisms remain unclear. Methods Effects of DHA on the proliferation, cell death, ROS and lipid ROS generation as well as reduced gluthione consumption were assessed in glioma cells with or without ferroptosis inhibitor. The biological mechanisms by which glioma cells attenuate the pro-ferroptotic effects of DHA were assessed using molecular methods. Results DHA induced ferroptosis in glioma cells, as characterized by iron-dependent cell death accompanied with ROS generation and lipid peroxidation. However, DHA treatment simultaneously activated a feedback pathway of ferroptosis by increasing the expression of heat shock protein family A (Hsp70) member 5 (HSPA5). Mechanistically, DHA caused endoplasmic reticulum (ER) stress in glioma cells, which resulted in the induction of HSPA5 expression by protein kinase R-like ER kinase (PERK)-upregulated activating transcription factor 4 (ATF4). Subsequent HSPA5 upregulation increased the expression and activity of glutathione peroxidase 4 (GPX4), which neutralized DHA-induced lipid peroxidation and thus protected glioma cells from ferroptosis. Inhibition of the PERK-ATF4-HSPA5-GPX4 pathway using siRNA or small molecules increased DHA sensitivity of glioma cells by increasing ferroptosis both in vitro and in vivo. Conclusions Collectively, these data suggested that ferroptosis might be a novel anticancer mechanism of DHA in glioma and HSPA5 may serve as a negative regulator of DHA-induced ferroptosis. Therefore, inhibiting the negative feedback pathway would be a promising therapeutic strategy to strengthen the anti-glioma activity of DHA.
abstractGer	Abstract Background Dihydroartemisinin (DHA) has been shown to exert anticancer activity through iron-dependent reactive oxygen species (ROS) generation, which is similar to ferroptosis, a novel form of cell death. However, whether DHA causes ferroptosis in glioma cells and the potential regulatory mechanisms remain unclear. Methods Effects of DHA on the proliferation, cell death, ROS and lipid ROS generation as well as reduced gluthione consumption were assessed in glioma cells with or without ferroptosis inhibitor. The biological mechanisms by which glioma cells attenuate the pro-ferroptotic effects of DHA were assessed using molecular methods. Results DHA induced ferroptosis in glioma cells, as characterized by iron-dependent cell death accompanied with ROS generation and lipid peroxidation. However, DHA treatment simultaneously activated a feedback pathway of ferroptosis by increasing the expression of heat shock protein family A (Hsp70) member 5 (HSPA5). Mechanistically, DHA caused endoplasmic reticulum (ER) stress in glioma cells, which resulted in the induction of HSPA5 expression by protein kinase R-like ER kinase (PERK)-upregulated activating transcription factor 4 (ATF4). Subsequent HSPA5 upregulation increased the expression and activity of glutathione peroxidase 4 (GPX4), which neutralized DHA-induced lipid peroxidation and thus protected glioma cells from ferroptosis. Inhibition of the PERK-ATF4-HSPA5-GPX4 pathway using siRNA or small molecules increased DHA sensitivity of glioma cells by increasing ferroptosis both in vitro and in vivo. Conclusions Collectively, these data suggested that ferroptosis might be a novel anticancer mechanism of DHA in glioma and HSPA5 may serve as a negative regulator of DHA-induced ferroptosis. Therefore, inhibiting the negative feedback pathway would be a promising therapeutic strategy to strengthen the anti-glioma activity of DHA.
abstract_unstemmed	Abstract Background Dihydroartemisinin (DHA) has been shown to exert anticancer activity through iron-dependent reactive oxygen species (ROS) generation, which is similar to ferroptosis, a novel form of cell death. However, whether DHA causes ferroptosis in glioma cells and the potential regulatory mechanisms remain unclear. Methods Effects of DHA on the proliferation, cell death, ROS and lipid ROS generation as well as reduced gluthione consumption were assessed in glioma cells with or without ferroptosis inhibitor. The biological mechanisms by which glioma cells attenuate the pro-ferroptotic effects of DHA were assessed using molecular methods. Results DHA induced ferroptosis in glioma cells, as characterized by iron-dependent cell death accompanied with ROS generation and lipid peroxidation. However, DHA treatment simultaneously activated a feedback pathway of ferroptosis by increasing the expression of heat shock protein family A (Hsp70) member 5 (HSPA5). Mechanistically, DHA caused endoplasmic reticulum (ER) stress in glioma cells, which resulted in the induction of HSPA5 expression by protein kinase R-like ER kinase (PERK)-upregulated activating transcription factor 4 (ATF4). Subsequent HSPA5 upregulation increased the expression and activity of glutathione peroxidase 4 (GPX4), which neutralized DHA-induced lipid peroxidation and thus protected glioma cells from ferroptosis. Inhibition of the PERK-ATF4-HSPA5-GPX4 pathway using siRNA or small molecules increased DHA sensitivity of glioma cells by increasing ferroptosis both in vitro and in vivo. Conclusions Collectively, these data suggested that ferroptosis might be a novel anticancer mechanism of DHA in glioma and HSPA5 may serve as a negative regulator of DHA-induced ferroptosis. Therefore, inhibiting the negative feedback pathway would be a promising therapeutic strategy to strengthen the anti-glioma activity of DHA.
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title_short	Dihydroartemisinin-induced unfolded protein response feedback attenuates ferroptosis via PERK/ATF4/HSPA5 pathway in glioma cells
url	https://doi.org/10.1186/s13046-019-1413-7 https://doaj.org/article/018c6c9bb2b44898bcbd00bd3481b804 http://link.springer.com/article/10.1186/s13046-019-1413-7 https://doaj.org/toc/1756-9966
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author2	Yanjun Mi Xiaofei Zhang Qian Ma Yucen Song Liwei Zhang Dandan Wang Jinliang Xing Benxin Hou Haolong Li Huan Jin Wei Du Zhengzhi Zou
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up_date	2024-07-03T20:41:32.673Z
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Dihydroartemisinin-induced unfolded protein response feedback attenuates ferroptosis via PERK/ATF4/HSPA5 pathway in glioma cells

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