DIRAS3 induces autophagy and enhances sensitivity to anti-autophagic therapy in KRAS-driven pancreatic and ovarian carcinomas.
Autophagy
; 20(3): 675-691, 2024 Mar.
Article
em En
| MEDLINE
| ID: mdl-38169324
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.Abbreviations AFR autophagic flux reporter; ATG autophagy related; CQ chloroquine; DCFDA 2'-7'-dichlorodihydrofluorescein diacetate; DIRAS3 DIRAS family GTPase 3; DOX doxycycline; KRAS KRAS proto-oncogene, LGSOC low-grade serous ovarian cancer; MiT/TFE microphthalmia family of transcription factors; NAC N-acetylcysteine; PDAC pancreatic ductal adenocarcinoma; ROS reactive oxygen species; TFEB transcription factor EB.
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Base de dados:
MEDLINE
Assunto principal:
Neoplasias Ovarianas
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Neoplasias Pancreáticas
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Carcinoma Ductal Pancreático
Tipo de estudo:
Diagnostic_studies
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Risk_factors_studies
Limite:
Female
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Humans
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article