Susceptibility of cervical cancer to dihydroartemisinin-induced ferritinophagy-dependent ferroptosis
The clinical therapeutics of cervical cancer is limited due to the drug resistance and metastasis of tumor. As a novel target for antitumor therapy, ferroptosis is deemed to be more susceptible for those cancer cells with resistance to apoptosis and chemotherapy. Dihydroartemisinin (DHA), the primar...
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Frontiers Media S.A.
2023-03-01
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| Series: | Frontiers in Molecular Biosciences |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fmolb.2023.1156062/full |
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| author | Hanqiang Shi Hanqiang Shi Lie Xiong Lie Xiong Guang Yan Shuqin Du Shuqin Du Jie Liu Yanbo Shi Yanbo Shi |
| author_facet | Hanqiang Shi Hanqiang Shi Lie Xiong Lie Xiong Guang Yan Shuqin Du Shuqin Du Jie Liu Yanbo Shi Yanbo Shi |
| author_sort | Hanqiang Shi |
| collection | DOAJ |
| description | The clinical therapeutics of cervical cancer is limited due to the drug resistance and metastasis of tumor. As a novel target for antitumor therapy, ferroptosis is deemed to be more susceptible for those cancer cells with resistance to apoptosis and chemotherapy. Dihydroartemisinin (DHA), the primary active metabolites of artemisinin and its derivatives, has exhibited a variety of anticancer properties with low toxicity. However, the role of DHA and ferroptosis in cervical cancer remained unclear. Here, we showed that DHA could time-dependently and dose-dependently inhibit the proliferation of cervical cancer cells, which could be alleviated by the inhibitors of ferroptosis rather than apoptosis. Further investigation confirmed that DHA treatment initiated ferroptosis, as evidenced by the accumulation of reactive oxygen species (ROS), malondialdehyde (MDA) and liquid peroxidation (LPO) levels and simultaneously depletion of glutathione peroxidase 4 (GPX4) and glutathione (GSH). Moreover, nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy was also induced by DHA leading to subsequent increases of intracellular labile iron pool (LIP), exacerbated the Fenton reaction resulting in excessive ROS production, and enhanced cervical cancer ferroptosis. Among them, we unexpectedly found that heme oxygenase-1 (HO-1) played an antioxidant role in DHA-induced cell death. In addition, the results of synergy analysis showed that the combination of DHA and doxorubicin (DOX) emerged a highly synergistic lethal effect for cervical cancer cells, which was related also to ferroptosis. Overall, our data revealed the molecular mechanisms that DHA triggered ferritinophagy-dependent ferroptosis and sensitized to DOX in cervical cancer, which may provide novel avenues for future therapy development. |
| first_indexed | 2024-04-09T20:19:43Z |
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| institution | Directory Open Access Journal |
| issn | 2296-889X |
| language | English |
| last_indexed | 2024-04-09T20:19:43Z |
| publishDate | 2023-03-01 |
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| series | Frontiers in Molecular Biosciences |
| spelling | doaj.art-53484792c2a84cc4a238fcba8685bc872023-03-31T06:36:00ZengFrontiers Media S.A.Frontiers in Molecular Biosciences2296-889X2023-03-011010.3389/fmolb.2023.11560621156062Susceptibility of cervical cancer to dihydroartemisinin-induced ferritinophagy-dependent ferroptosisHanqiang Shi0Hanqiang Shi1Lie Xiong2Lie Xiong3Guang Yan4Shuqin Du5Shuqin Du6Jie Liu7Yanbo Shi8Yanbo Shi9Central Laboratory of Molecular Medicine Research Center, Jiaxing Traditional Chinese Medicine Hospital Affiliated to Zhejiang Chinese Medical University, Jiaxing, ChinaJiaxing Key Laboratory of Diabetic Angiopathy Research, Jiaxing, ChinaCentral Laboratory of Molecular Medicine Research Center, Jiaxing Traditional Chinese Medicine Hospital Affiliated to Zhejiang Chinese Medical University, Jiaxing, ChinaJiaxing Key Laboratory of Diabetic Angiopathy Research, Jiaxing, ChinaDepartment of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, ChinaCentral Laboratory of Molecular Medicine Research Center, Jiaxing Traditional Chinese Medicine Hospital Affiliated to Zhejiang Chinese Medical University, Jiaxing, ChinaSchool of Pharmacy, Zhejiang University of Technology, Hangzhou, ChinaOncology Department, Jiaxing Traditional Chinese Medicine Hospital Affiliated to Zhejiang Chinese Medical University, Jiaxing, ChinaCentral Laboratory of Molecular Medicine Research Center, Jiaxing Traditional Chinese Medicine Hospital Affiliated to Zhejiang Chinese Medical University, Jiaxing, ChinaJiaxing Key Laboratory of Diabetic Angiopathy Research, Jiaxing, ChinaThe clinical therapeutics of cervical cancer is limited due to the drug resistance and metastasis of tumor. As a novel target for antitumor therapy, ferroptosis is deemed to be more susceptible for those cancer cells with resistance to apoptosis and chemotherapy. Dihydroartemisinin (DHA), the primary active metabolites of artemisinin and its derivatives, has exhibited a variety of anticancer properties with low toxicity. However, the role of DHA and ferroptosis in cervical cancer remained unclear. Here, we showed that DHA could time-dependently and dose-dependently inhibit the proliferation of cervical cancer cells, which could be alleviated by the inhibitors of ferroptosis rather than apoptosis. Further investigation confirmed that DHA treatment initiated ferroptosis, as evidenced by the accumulation of reactive oxygen species (ROS), malondialdehyde (MDA) and liquid peroxidation (LPO) levels and simultaneously depletion of glutathione peroxidase 4 (GPX4) and glutathione (GSH). Moreover, nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy was also induced by DHA leading to subsequent increases of intracellular labile iron pool (LIP), exacerbated the Fenton reaction resulting in excessive ROS production, and enhanced cervical cancer ferroptosis. Among them, we unexpectedly found that heme oxygenase-1 (HO-1) played an antioxidant role in DHA-induced cell death. In addition, the results of synergy analysis showed that the combination of DHA and doxorubicin (DOX) emerged a highly synergistic lethal effect for cervical cancer cells, which was related also to ferroptosis. Overall, our data revealed the molecular mechanisms that DHA triggered ferritinophagy-dependent ferroptosis and sensitized to DOX in cervical cancer, which may provide novel avenues for future therapy development.https://www.frontiersin.org/articles/10.3389/fmolb.2023.1156062/fullcervical cancerdihydroartemisininferroptosisferritinophagyheme oxygenase-1doxorubicin |
| spellingShingle | Hanqiang Shi Hanqiang Shi Lie Xiong Lie Xiong Guang Yan Shuqin Du Shuqin Du Jie Liu Yanbo Shi Yanbo Shi Susceptibility of cervical cancer to dihydroartemisinin-induced ferritinophagy-dependent ferroptosis Frontiers in Molecular Biosciences cervical cancer dihydroartemisinin ferroptosis ferritinophagy heme oxygenase-1 doxorubicin |
| title | Susceptibility of cervical cancer to dihydroartemisinin-induced ferritinophagy-dependent ferroptosis |
| title_full | Susceptibility of cervical cancer to dihydroartemisinin-induced ferritinophagy-dependent ferroptosis |
| title_fullStr | Susceptibility of cervical cancer to dihydroartemisinin-induced ferritinophagy-dependent ferroptosis |
| title_full_unstemmed | Susceptibility of cervical cancer to dihydroartemisinin-induced ferritinophagy-dependent ferroptosis |
| title_short | Susceptibility of cervical cancer to dihydroartemisinin-induced ferritinophagy-dependent ferroptosis |
| title_sort | susceptibility of cervical cancer to dihydroartemisinin induced ferritinophagy dependent ferroptosis |
| topic | cervical cancer dihydroartemisinin ferroptosis ferritinophagy heme oxygenase-1 doxorubicin |
| url | https://www.frontiersin.org/articles/10.3389/fmolb.2023.1156062/full |
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