DIRAS3 Induces Autophagy and Enhances Sensitivity to Anti-Autophagic Therapy in KRAS-Driven Pancreatic and Ovarian Carcinomas

Authors

Gamze Bildik
Joshua P Gray
Weiqun Mao
Hailing Yang
Rumeysa Ozyurt
Vivian R Orellana
Olivier De Wever
Mark S Carey
Robert C Bast
Zhen Lu

Publication Date

3-1-2024

Journal

Autophagy

Abstract

Pancreatic ductal adenocarcinoma (PDAC) and low-grade ovarian cancer (LGSOC) are characterized by the prevalence of KRAS oncogene mutations. DIRAS3 is the first endogenous non-RAS protein that heterodimerizes with RAS, disrupts RAS clustering, blocks RAS signaling, and inhibits cancer cell growth. Here, we found that DIRAS3-mediated KRAS inhibition induces ROS-mediated apoptosis in PDAC and LGSOC cells with KRAS mutations, but not in cells with wild-type KRAS, by downregulating NFE2L2/Nrf2 transcription, reducing antioxidants, and inducing oxidative stress. DIRAS3 also induces cytoprotective macroautophagy/autophagy that may protect mutant KRAS cancer cells from oxidative stress, by inhibiting mutant KRAS, activating the STK11/LKB1-PRKAA/AMPK pathway, increasing lysosomal CDKN1B/p27 localization, and inducing autophagic gene expression. Treatment with chloroquine or the novel dimeric chloroquine analog DC661 significantly enhances DIRAS3-mediated inhibition of mutant KRAS tumor cell growth in vitro and in vivo. Taken together, our study demonstrates that DIRAS3 plays a critical role in regulating mutant KRAS-driven oncogenesis in PDAC and LGSOC.

Keywords

Female, Humans, Proto-Oncogene Proteins p21(ras), Reactive Oxygen Species, Cell Line, Tumor, Autophagy, Ovarian Neoplasms, Pancreatic Neoplasms, Carcinoma, Pancreatic Ductal, Chloroquine

DOI

10.1080/15548627.2023.2299516

PMID

38169324

PMCID

PMC10936598

PubMedCentral® Posted Date

1-3-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes