Inhibition of KRAS-dependent lung cancer cell growth by deltarasin: Blockage of autophagy increases its cytotoxicity article

Elaine Lai Han Leung, Lian Xiang Luo, Zhong Qiu Liu, Vincent Kam Wai Wong, Lin Lin Lu, Ying Xie, Ni Zhang, Yuan Qing Qu, Xing Xing Fan, Ying Li, Min Huang, Dai Kai Xiao, Jun Huang, Yan Ling Zhou, Jian Xing He, Jian Ding, Xiao Jun Yao, David C. Ward, Liang Liu

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

Abstract

Deltarasin is a recently identified small molecule that can inhibit KRAS-PDEδ interactions by binding to a hydrophobic pocket on PDEδ, resulting in the impairment of cell growth, KRAS activity, and RAS/RAF signaling in human pancreatic ductal adenocarcinoma cell lines. Since KRAS mutations are the most common oncogene mutations in lung adenocarcinomas, implicated in over 30% of all lung cancer cases, we examined the ability of deltarasin to inhibit KRAS-dependent lung cancer cell growth. Here, for the first time, we document that deltarasin produces both apoptosis and autophagy in KRAS-dependent lung cancer cells in vitro and inhibits lung tumor growth in vivo. Deltarasin induces apoptosis by inhibiting the interaction of with PDEδ and its downstream signaling pathways, while it induces autophagy through the AMPK-mTOR signaling pathway. Importantly, the autophagy inhibitor, 3-methyl adenine (3-MA) markedly enhances deltarasin-induced apoptosis via elevation of reactive oxygen species (ROS). In contrast, inhibition of ROS by N-acetylcysteine (NAC) significantly attenuated deltarasin-induced cell death. Collectively, these observations suggest that the anti-cancer cell activity of deltarasin can be enhanced by simultaneously blocking "tumor protective" autophagy, but inhibited if combined with an anti-oxidant.

Original languageEnglish (US)
Article number216
JournalCell Death and Disease
Volume9
Issue number2
DOIs
StatePublished - Feb 1 2018
Externally publishedYes

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

Fingerprint

Dive into the research topics of 'Inhibition of KRAS-dependent lung cancer cell growth by deltarasin: Blockage of autophagy increases its cytotoxicity article'. Together they form a unique fingerprint.

Cite this