Aberrant ROS Served as an Acquired Vulnerability of Cisplatin-resistant Lung Cancer
Abstract BackgroundLung cancer has become a global health issue in recent decades. Despite of high rate of resistance, cisplatin-base chemotherapy is still the main treatment of lung cancer patients who are not suitable for TKI-based targeted therapy and immunotherapy. Thus, overcoming cisplatin resistance is urgently needed.MethodsA small panel is established to screen chemicals and compounds overcoming cisplatin resistance. Survival fractions as well as proliferation are determined by MTT assay. Colony formation assay, JC-1 assay, EdU assay, ROS assay as well as apoptosis and cell cycle assay are performed to verify vitalities of different groups. Quantifications of NADP+/NADPH and GSH/GSSG are carried out according to standard protocols. Xenograft model is generated to evaluate the in vivo role of APR-246.ResultsIn this study, we identify NADPH metabolism and reactive oxygen species (ROS) levels as the main cause accounting for cisplatin resistance of H460. Based on a small panel consisting common chemotherapy drugs and compounds, APR-246 is proved an effective compound specifically inhibiting proliferation and colony formation of cisplatin resistant H460 (H460-Cis) cells. APR-246 significantly causes G0/G1 accumulation and S phase inhibition of H460-Cis cells. Besides, APR-246 can obviously lead to severe mitochondria dysfunction as well as elevated apoptosis by altering apoptosis-related protein expressions in H460-Cis cells. Further study proves that it is the aberrant ROS levels as well as NRF2/SLC7A11/GSH axis dysfunction accounting for the specific anti-tumor effects of APR-246. Mechanistically, NRF2 is specifically ubiquitylated degraded in APR-246 treated H460-Cis cells, which in turn decrease NRF2/SLC7A11/GSH axis activity.ConclusionOur study uncovered new insights into the biology driving cisplatin resistance of lung cancer and highlights potentials of APR-246 as future therapeutic agents again cisplatin resistance..
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Preprint| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
ResearchSquare.com - (2021) vom: 17. März Zur Gesamtaufnahme - year:2021 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Xin, Qian [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| doi: |
10.21203/rs.3.rs-141062/v1 |
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| PPN (Katalog-ID): |
XRA034184406 |
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| 520 | |a Abstract BackgroundLung cancer has become a global health issue in recent decades. Despite of high rate of resistance, cisplatin-base chemotherapy is still the main treatment of lung cancer patients who are not suitable for TKI-based targeted therapy and immunotherapy. Thus, overcoming cisplatin resistance is urgently needed.MethodsA small panel is established to screen chemicals and compounds overcoming cisplatin resistance. Survival fractions as well as proliferation are determined by MTT assay. Colony formation assay, JC-1 assay, EdU assay, ROS assay as well as apoptosis and cell cycle assay are performed to verify vitalities of different groups. Quantifications of NADP+/NADPH and GSH/GSSG are carried out according to standard protocols. Xenograft model is generated to evaluate the in vivo role of APR-246.ResultsIn this study, we identify NADPH metabolism and reactive oxygen species (ROS) levels as the main cause accounting for cisplatin resistance of H460. Based on a small panel consisting common chemotherapy drugs and compounds, APR-246 is proved an effective compound specifically inhibiting proliferation and colony formation of cisplatin resistant H460 (H460-Cis) cells. APR-246 significantly causes G0/G1 accumulation and S phase inhibition of H460-Cis cells. Besides, APR-246 can obviously lead to severe mitochondria dysfunction as well as elevated apoptosis by altering apoptosis-related protein expressions in H460-Cis cells. Further study proves that it is the aberrant ROS levels as well as NRF2/SLC7A11/GSH axis dysfunction accounting for the specific anti-tumor effects of APR-246. Mechanistically, NRF2 is specifically ubiquitylated degraded in APR-246 treated H460-Cis cells, which in turn decrease NRF2/SLC7A11/GSH axis activity.ConclusionOur study uncovered new insights into the biology driving cisplatin resistance of lung cancer and highlights potentials of APR-246 as future therapeutic agents again cisplatin resistance. | ||
| 700 | 1 | |a Ji, Qinghong |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Ying |e verfasserin |4 aut | |
| 700 | 1 | |a Ma, Weihong |e verfasserin |4 aut | |
| 700 | 1 | |a Tian, Baoqing |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Yanli |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Yunsong |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Fei |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Ran |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Xingwu |e verfasserin |4 aut | |
| 700 | 1 | |a Yuan, Jupeng |e verfasserin |4 aut | |
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