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...
Ausführliche Beschreibung
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] |
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E-Artikel |
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Sprache: |
Englisch |
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2019 |
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Übergeordnetes Werk: |
In: Journal of Experimental & Clinical Cancer Research - BMC, 2008, 38(2019), 1, Seite 16 |
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Übergeordnetes Werk: |
volume:38 ; year:2019 ; number:1 ; pages:16 |
Links: |
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DOI / URN: |
10.1186/s13046-019-1413-7 |
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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 | |
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700 | 0 | |a Wei Du |e verfasserin |4 aut | |
700 | 0 | |a Zhengzhi Zou |e verfasserin |4 aut | |
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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 |
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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 |
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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 |
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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 |
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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 |
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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 |
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Dihydroartemisinin-induced unfolded protein response feedback attenuates ferroptosis via PERK/ATF4/HSPA5 pathway in glioma cells |
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Dihydroartemisinin-induced unfolded protein response feedback attenuates ferroptosis via PERK/ATF4/HSPA5 pathway in glioma cells |
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Yibing Chen |
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Journal of Experimental & Clinical Cancer Research |
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Journal of Experimental & Clinical Cancer Research |
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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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dihydroartemisinin-induced unfolded protein response feedback attenuates ferroptosis via perk/atf4/hspa5 pathway in glioma cells |
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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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Dihydroartemisinin-induced unfolded protein response feedback attenuates ferroptosis via PERK/ATF4/HSPA5 pathway in glioma cells |
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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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