SREBP1-SCD1 enhanced MUFAs Biosynthesis drives Nutrient Deprived Pancreatic cancer cell Ferroptosis Resistance

Background: As the most disastrous tumor microenvironment of pancreatic Cancer, nutrient deprivation determined various cancer Cell Biology, especially the cell death resistance. Our objective is to elucidate the role of nutrient deprivation in Ferroptosis resistance of pancreatic Cancer cells and to explore potential therapeutic strategies to overcome it. Methods: To replicate the nutrient-deprived tumor microenvironment, pancreatic Cancer cell lines (PANC1 and Patu8988T) were cultured in Dulbecco's Modified Eagle Medium (DMEM) supplemented with 2% Fetal Bovine Serum (FBS). Ferroptosis was assessed by Cell Counting Kit-8 (CCK8), Malondialdehyde (MDA) assay, and C11 BODIPY staining. The signaling activity was assessed via western blot and quantitative reverse transcription polymerase chain reaction (qRT-PCR), respectively. Results: Ferroptosis inducers promoted pancreatic Cancer cell death could be significantly reversed under nutrient deprivation condition. Nutrient deprivation upregulated the expression of SREBP1 and SCD1, leading to increased intracellular levels of monounsaturated fatty acids (MUFAs). Genetic knockdown of SREBP1 or SCD1, as well as treatment with rapamycin (an mTOR Inhibitor), reversed the nutrient deprivation induced increase in mature SREBP1 and SCD1 expression and restored lipid peroxidation both in vitro and in vivo. The synergistic application of sorafenib and rapamycin yielded a profoundly efficacious therapeutic outcome in vivo. Conclusion: Our findings demonstrate that nutrient-deprived pancreatic Cancer cells adaptively enhance MUFA biosynthesis through the SREBP1-SCD1 axis, conferring resistance to Ferroptosis. This resistance can be effectively overcome by combination therapy with sorafenib and rapamycin, offering a promising strategy to target the Ferroptosis vulnerability shaped by the pancreatic tumor microenvironment.

Ferroptosis; MUFAs; nutrient deprivation; pancreatic cancer.; rapamycin.