Abstract 6249: PERK arm of UPR selectively regulates ferroptosis in colon cancer cells by modulating the expression of system xc - (SLC7A11)

Ferroptosis, a genetically and biochemically distinct form of programmed cell death, is characterized by iron-dependent accumulation of lipid peroxides. Ferroptosis is induced in cancer cells by inhibition of lipid peroxide quencher GPx4. System xc - imports cystine into cytosol for the biosynthesis of glutathione. Tumor cells that are resistant to chemotherapeutic drugs called ‘drug tolerant’ or ‘Persister’ cells which have distinct vulnerability towards iron mediated cell death or ferroptosis. Unfolded Protein Response (UPR) plays critical role for cancer cells to become drug tolerant. Tweaking the balance of UPR to make drug tolerant cells susceptible to Ferroptotic cell death could be an attractive therapeutic strategy. To decipher the emerging contribution of ER-stress in ferroptosis, we investigated the status of UPR following treatment of potent ferroptosis inducer RSL3 (Ras Selective Lethal) in colon cancer cells. We observed an overall up-regulation of UPR activators (ATF6, IRE1α and PERK) and their downstream effectors along with a marked overexpression of cystine-glutamate transporter (System xc -). To further delineate the contribution of particular UPR arm in modulating System xc - expression and subsequent ferroptosis, we made stable knock down cells of each UPR arm and discovered that PERK is selective and critical in inducing ferroptosis in colon cancer cells. Loss of PERK function not only promotes ferroptosis via increasing lipid peroxidation but also limits in vivo tumor growth in colon xenograft model. Further, we find that low PERK expression is associated with higher patient survival as per TCGA COLON CANCER (COAD) database. Overall, our experimental data indicate that PERK is a negative regulator of ferroptosis and genetic silencing of PERK sensitizes colon cancer cells to selective Ferroptotic cell death. Therefore, small molecule PERK inhibitors hold huge promise as novel therapeutics that can sensitize apoptosis resistant cancer cells towards Ferroptotic cell death. Citation Format: Krishan K. Saini, Priyank Chaturvedi, Ayushi Verma, Mushtaq A. Nengroo, Abhipsa Sinha, Akhilesh Singh, Sanjeev Meena, Muqtada A. Khan, Manish P. Singh, Dipak Datta. PERK arm of UPR selectively regulates ferroptosis in colon cancer cells by modulating the expression of system xc - (SLC7A11) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6249.