MLN4924 suppresses pancreatic cancer progression and enhances chemosensitivity to gemcitabine by targeting the PTGS2/EGFR–PI3K/Akt/mTOR signaling axis

Pancreatic cancer is a highly lethal digestive malignancy characterized by insidious onset and rapid progression. Approximately 80% of patients are diagnosed at an advanced stage with metastasis, missing the opportunity for radical surgery, and chemotherapy remains the main palliative treatment. Its incidence is rising annually, highlighting the urgent need for novel therapeutic strategies. MLN4924 (Pevonedistat), a first-in-class NEDD8-activating enzyme inhibitor, exhibits promising antitumor activity in various cancers, yet its role and mechanism in pancreatic cancer remain largely undefined. Potential hub targets of MLN4924 in pancreatic cancer were screened using Swiss Target-Prediction and Gene-Cards databases. Western blot was used to detect the expression of hub genes and the activity of the prostaglandin G/H synthase 2 (PTGS2)-epidermal growth factor receptor (EGFR)-phosphatidylinositol 3‐kinase (PI3K)/RAC‐gamma serine/threonine‐protein kinase (Akt)/serine/threonine‐protein kinase (mTOR) axis following MLN4924 intervention. CCK-8, EdU, and wound-healing assays were performed to evaluate cell proliferation and migration after MLN4924 treatment. Furthermore, PTGS2 knockdown via siRNA transfection was applied to verify its effects on EGFR-PI3K/Akt/mTOR pathway activity, malignant phenotypes, and gemcitabine sensitivity in pancreatic cancer cells. We identified four hub genes (CASP3, PTGS2, MMP9, and MAPK8) of MLN4924 in pancreatic cancer. We validated that MLN4924 suppressed proliferation and migration of pancreatic cancer cells, downregulated hub gene expression, and inhibited the PTGS2-mediated PI3K/AKT/mTOR signaling pathway. Furthermore, siRNA-mediated silencing of PTGS2 phenocopied the inhibitory effects of MLN4924 on cell proliferation. Notably, both MLN4924 and PTGS2 knockdown significantly enhanced the chemosensitivity of pancreatic cancer cells to gemcitabine. Collectively, our results demonstrate that MLN4924 exerts antitumor effects in pancreatic cancer by targeting the PTGS2-EGFR-PI3K/AKT/mTOR axis, providing a mechanistic rationale for its clinical application in pancreatic cancer therapy.