Aberrant ROS Served as an Acquired Vulnerability of Cisplatin-Resistant Lung Cancer
Copyright © 2022 Qian Xin et al..
Lung cancer has become a global health issue in recent decades. Approximately 80-85% of cases are non-small-cell lung cancer (NSCLC). Despite the high rate of resistance, cisplatin-base chemotherapy is still the main treatment for NSCLC patients. Thus, overcoming cisplatin resistance is urgently needed in NSCLC therapy. In this study, we identify NADPH metabolism and reactive oxygen species (ROS) levels as the main causes accounting for cisplatin resistance. Based on a small panel consisting of common chemotherapy drugs or compounds, APR-246 is proved to be an effective compound targeting cisplatin-resistant NSCLC cells. APR-246 specially inhibits proliferation and colony formation of cisplatin-resistant cells. In details, APR-246 can significantly cause G0/G1 accumulation and S phase arrest of cisplatin resistant cells and gives rise to severe mitochondria dysfunction as well as elevated apoptosis. Further study proves that it is the aberrant ROS levels as well as NRF2/SLC7A11/GSH axis dysfunction accounting for the specific antitumor effects of APR-246. Scavenging ROS with N-acetylcysteine (NAC) disrupts the inhibitory effect of APR-246 on cisplatin-resistant cells. Mechanistically, NRF2 is specifically degraded by the proteasome following its own ubiquitylation in APR-246-treated cisplatin-resistant cells, which in turn decreases NRF2/SLC7A11/GSH axis activity. Our study provides new insights into the biology driving cisplatin resistance of lung cancer and highlights APR-246 as a potential therapeutic reagent for overcoming cisplatin resistance.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2022 |
|---|---|
| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:2022 |
|---|---|
| Enthalten in: |
Oxidative medicine and cellular longevity - 2022(2022) vom: 31., Seite 1112987 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Xin, Qian [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Antineoplastic Agents |
|---|
| Anmerkungen: |
Date Completed 01.07.2022 Date Revised 16.07.2022 published: Electronic-eCollection Citation Status MEDLINE |
|---|
| doi: |
10.1155/2022/1112987 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM342908898 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM342908898 | ||
| 003 | DE-627 | ||
| 005 | 20231226015206.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2022 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1155/2022/1112987 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1142.xml |
| 035 | |a (DE-627)NLM342908898 | ||
| 035 | |a (NLM)35770045 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Xin, Qian |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Aberrant ROS Served as an Acquired Vulnerability of Cisplatin-Resistant Lung Cancer |
| 264 | 1 | |c 2022 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 01.07.2022 | ||
| 500 | |a Date Revised 16.07.2022 | ||
| 500 | |a published: Electronic-eCollection | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2022 Qian Xin et al. | ||
| 520 | |a Lung cancer has become a global health issue in recent decades. Approximately 80-85% of cases are non-small-cell lung cancer (NSCLC). Despite the high rate of resistance, cisplatin-base chemotherapy is still the main treatment for NSCLC patients. Thus, overcoming cisplatin resistance is urgently needed in NSCLC therapy. In this study, we identify NADPH metabolism and reactive oxygen species (ROS) levels as the main causes accounting for cisplatin resistance. Based on a small panel consisting of common chemotherapy drugs or compounds, APR-246 is proved to be an effective compound targeting cisplatin-resistant NSCLC cells. APR-246 specially inhibits proliferation and colony formation of cisplatin-resistant cells. In details, APR-246 can significantly cause G0/G1 accumulation and S phase arrest of cisplatin resistant cells and gives rise to severe mitochondria dysfunction as well as elevated apoptosis. Further study proves that it is the aberrant ROS levels as well as NRF2/SLC7A11/GSH axis dysfunction accounting for the specific antitumor effects of APR-246. Scavenging ROS with N-acetylcysteine (NAC) disrupts the inhibitory effect of APR-246 on cisplatin-resistant cells. Mechanistically, NRF2 is specifically degraded by the proteasome following its own ubiquitylation in APR-246-treated cisplatin-resistant cells, which in turn decreases NRF2/SLC7A11/GSH axis activity. Our study provides new insights into the biology driving cisplatin resistance of lung cancer and highlights APR-246 as a potential therapeutic reagent for overcoming cisplatin resistance | ||
| 650 | 4 | |a Journal Article | |
| 650 | 7 | |a Antineoplastic Agents |2 NLM | |
| 650 | 7 | |a NF-E2-Related Factor 2 |2 NLM | |
| 650 | 7 | |a Reactive Oxygen Species |2 NLM | |
| 650 | 7 | |a Cisplatin |2 NLM | |
| 650 | 7 | |a Q20Q21Q62J |2 NLM | |
| 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 | |
| 773 | 0 | 8 | |i Enthalten in |t Oxidative medicine and cellular longevity |d 2008 |g 2022(2022) vom: 31., Seite 1112987 |w (DE-627)NLM191313068 |x 1942-0994 |7 nnns |
| 773 | 1 | 8 | |g volume:2022 |g year:2022 |g day:31 |g pages:1112987 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1155/2022/1112987 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 2022 |j 2022 |b 31 |h 1112987 | ||