Quantitative Proteomic Profiling Identifies SOX8 as Novel Regulator of Drug Resistance in Gestational Trophoblastic Neoplasia
The development of drug resistance remains one of the major challenges to current chemotherapeutic regimens in gestational trophoblastic neoplasia (GTN). Further understanding on the mechanisms of drug resistance would help to develop more effective therapy to treat GTN. Herein, tandem mass tag-base...
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Frontiers Media S.A.
2020-04-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fonc.2020.00557/full |
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| author | Fu Jun Fu Jun Zheng Peng Zheng Peng Yi Zhang Yi Zhang Dazun Shi Dazun Shi |
| author_facet | Fu Jun Fu Jun Zheng Peng Zheng Peng Yi Zhang Yi Zhang Dazun Shi Dazun Shi |
| author_sort | Fu Jun |
| collection | DOAJ |
| description | The development of drug resistance remains one of the major challenges to current chemotherapeutic regimens in gestational trophoblastic neoplasia (GTN). Further understanding on the mechanisms of drug resistance would help to develop more effective therapy to treat GTN. Herein, tandem mass tag-based (TMT) quantitative proteomic technique was used to establish drug resistance-related proteomic profiles in chemoresistant GTN cell models (JEG3/MTX, JEG3/VP16, JEG3/5-Fu). In total, we identified 5,704 protein groups, among which 4,997 proteins were quantified in JEG3 and its chemoresistant sublines. Bioinformatics analysis revealed that multiple biological processes/molecular pathways/signaling networks were involved in the regulation of drug resistance in chemoresistant JEG3 sublines. SOX8 was upregulated in all the three chemoresistant sublines, and its function was further investigated. Knockdown of SOX8 significantly reduced cell viability, impaired soft agar clonogenesis, and increased caspase-3 activities after drug treatment in JEG3 chemoresistant sublines. In addition, over-expression of SOX8 promoted cell survival, enhanced soft agar clonogenesis, and attenuated caspase-3 activities after drug treatment in GTN cells. Importantly, SOX8 might be a potential regulator of reactive oxygen species (ROS) homeostasis, as SOX8 regulated the expression of antioxidant enzymes (GPX1, HMOX1) and reduced drug-induced ROS accumulation in GTN cell models. Collectively, SOX8 might promote drug resistance through attenuating the accumulation of ROS induced by chemotherapeutic drugs in GTN cells. Targeting SOX8 might be useful to sensitize GTN cells to chemotherapy. |
| first_indexed | 2024-12-10T16:13:20Z |
| format | Article |
| id | doaj.art-467af27bec924a838c34a471b03ea688 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-10T16:13:20Z |
| publishDate | 2020-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-467af27bec924a838c34a471b03ea6882022-12-22T01:42:03ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2020-04-011010.3389/fonc.2020.00557500367Quantitative Proteomic Profiling Identifies SOX8 as Novel Regulator of Drug Resistance in Gestational Trophoblastic NeoplasiaFu Jun0Fu Jun1Zheng Peng2Zheng Peng3Yi Zhang4Yi Zhang5Dazun Shi6Dazun Shi7Department of Oncology, Xiangya Hospital, Central South University, Changsha, ChinaDepartment of Neurosurgery, Sanbo Brain Hospital, Capital Medical University, Beijing, ChinaDepartment of Gynecology and Obstetrics, Xiangya Hospital, Central South University, Changsha, ChinaGynecological Oncology Research and Engineering Center of Hunan Province, Changsha, ChinaDepartment of Gynecology and Obstetrics, Xiangya Hospital, Central South University, Changsha, ChinaGynecological Oncology Research and Engineering Center of Hunan Province, Changsha, ChinaDepartment of Gynecology and Obstetrics, Xiangya Hospital, Central South University, Changsha, ChinaGynecological Oncology Research and Engineering Center of Hunan Province, Changsha, ChinaThe development of drug resistance remains one of the major challenges to current chemotherapeutic regimens in gestational trophoblastic neoplasia (GTN). Further understanding on the mechanisms of drug resistance would help to develop more effective therapy to treat GTN. Herein, tandem mass tag-based (TMT) quantitative proteomic technique was used to establish drug resistance-related proteomic profiles in chemoresistant GTN cell models (JEG3/MTX, JEG3/VP16, JEG3/5-Fu). In total, we identified 5,704 protein groups, among which 4,997 proteins were quantified in JEG3 and its chemoresistant sublines. Bioinformatics analysis revealed that multiple biological processes/molecular pathways/signaling networks were involved in the regulation of drug resistance in chemoresistant JEG3 sublines. SOX8 was upregulated in all the three chemoresistant sublines, and its function was further investigated. Knockdown of SOX8 significantly reduced cell viability, impaired soft agar clonogenesis, and increased caspase-3 activities after drug treatment in JEG3 chemoresistant sublines. In addition, over-expression of SOX8 promoted cell survival, enhanced soft agar clonogenesis, and attenuated caspase-3 activities after drug treatment in GTN cells. Importantly, SOX8 might be a potential regulator of reactive oxygen species (ROS) homeostasis, as SOX8 regulated the expression of antioxidant enzymes (GPX1, HMOX1) and reduced drug-induced ROS accumulation in GTN cell models. Collectively, SOX8 might promote drug resistance through attenuating the accumulation of ROS induced by chemotherapeutic drugs in GTN cells. Targeting SOX8 might be useful to sensitize GTN cells to chemotherapy.https://www.frontiersin.org/article/10.3389/fonc.2020.00557/fullgestational trophoblastic neoplasiadrug resistancequantitative proteomicsSOX8reactive oxygen species |
| spellingShingle | Fu Jun Fu Jun Zheng Peng Zheng Peng Yi Zhang Yi Zhang Dazun Shi Dazun Shi Quantitative Proteomic Profiling Identifies SOX8 as Novel Regulator of Drug Resistance in Gestational Trophoblastic Neoplasia Frontiers in Oncology gestational trophoblastic neoplasia drug resistance quantitative proteomics SOX8 reactive oxygen species |
| title | Quantitative Proteomic Profiling Identifies SOX8 as Novel Regulator of Drug Resistance in Gestational Trophoblastic Neoplasia |
| title_full | Quantitative Proteomic Profiling Identifies SOX8 as Novel Regulator of Drug Resistance in Gestational Trophoblastic Neoplasia |
| title_fullStr | Quantitative Proteomic Profiling Identifies SOX8 as Novel Regulator of Drug Resistance in Gestational Trophoblastic Neoplasia |
| title_full_unstemmed | Quantitative Proteomic Profiling Identifies SOX8 as Novel Regulator of Drug Resistance in Gestational Trophoblastic Neoplasia |
| title_short | Quantitative Proteomic Profiling Identifies SOX8 as Novel Regulator of Drug Resistance in Gestational Trophoblastic Neoplasia |
| title_sort | quantitative proteomic profiling identifies sox8 as novel regulator of drug resistance in gestational trophoblastic neoplasia |
| topic | gestational trophoblastic neoplasia drug resistance quantitative proteomics SOX8 reactive oxygen species |
| url | https://www.frontiersin.org/article/10.3389/fonc.2020.00557/full |
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