PIM1 protects pancreatic ductal cancer cells from glucose deprivation-induced oxidative stress via OXR1 phosphorylation

Abstract

Limited nutrient availability in pancreatic ductal adenocarcinoma (PDAC), due to its dense extracellular matrix, presents a significant metabolic challenge that tumor cells must overcome to survive oxidative stress-induced cell death. Here, we found that PIM1, a serine/threonine kinase, is upregulated in PDAC tumors and serves as a poor prognostic indicator. Although PIM1 does not significantly affect PDAC cell proliferation, it is essential for protecting cells from glucose deprivation-induced cell death. Mechanistically, PIM1 interacts with the antioxidant protein OXR1 (oxidation resistance protein 1) and promotes its phosphorylation at serine 91. This modification mitigates oxidative stress, preserves mitochondrial morphology, and ultimately protects PDAC cells from glucose deprivation-induced cell death. Moreover, glucose deprivation activates AMPK, which in turn stabilizes PIM1 by protecting it from ubiquitin-mediated protein degradation. In contrast, AMPK inhibition reduces PIM1 level and abolishes the survival difference between cells with and without PIM1 depletion. Collectively, our findings reveal a critical role of PIM1 in PDAC cell survival under nutrient stress and identify PIM1 as a potential therapeutic target for PDAC.