Overcoming chemoresistance to b-raf inhibitor in melanoma via targeted inhibition of phosphoenolpyruvate carboxykinase1 using 3-mercaptopropionic acid. Issue 5 (2nd May 2022)

• Record Type: Journal Article
• Authors: Ren, Ming; Wang, Lu; Gao, Zi-Xu; Deng, Xin-Yi; Shen, Kang-Jie; Li, Yan-Lin; Ding, Yi-Teng; Wei, Chuan-Yuan; Gu, Jian-Ying
• Is Part Of: Bioengineered. Volume 13:Issue 5(2022)
• Page Start: 13571
• Page End: 13586
• Publication Date: 2022-05-02
• Subjects: B-raf -- resistance -- melanoma -- PCK1 -- 3-MPA -- ROS; Biomedical engineering -- Periodicals; Biotechnology -- Periodicals; Microbiology -- Periodicals; 660.6
• DOI: 10.1080/21655979.2022.2080385
• Languages: English
• ISSNs: 2165-5987

Abstract

ABSTRACT: The resistance of melanoma to BRAF inhibitors remains a tough clinical challenge. In order to explore the underlying mechanism of drug resistance in melanoma, we established the resistant cell line to vemurafenib, and assessed the changes of drug-resistant cells on proliferation, apoptosis, oxidative stress and tumor stemness. Our results suggest that phosphoenolpyruvate carboxykinase1 (PCK1) is activated and inhibits the oxidative stress caused by vemurafenib in drug-resistant cells. Long term treatment of vemurafenib increases the expression of PCK1 which reduces the production of reactive oxygen species (ROS) by activating PI3K/Akt pathway. After the inhibition of PCK1 by 3-mercaptopropionic acid (3-MPA), the therapeutic sensitivity of vemurafenib is restored. In conclusion, this study disclosed that drug-resistant cells appeared to regulate their own proliferation, oxidative stress and tumor dryness by activating Akt/PCK1/ROS pathway, and shed new insights into acquiring drug resistance in melanoma. Graphical Abstract: uf0001