Abstract 196: Acetylcholine enhances HIF-1α expression in pancreatic cancer cells under hypoxia through nAchR-α7/PDPK1/YAP signaling pathway

Abstract The pancreas has a high distribution of the autonomic nervous system. The role of the autonomic nervous system in pancreatic ductal adenocarcinoma development has been addressed in recent studies. HIF-1 regulates the expression of genes involved in angiogenesis, metastasis, tumor growth, chemoresistance and radioresistance, underscoring the growing interest in targeting HIF-1 for cancer control. In this study, we investigated the molecular mechanisms underlying the neurotransmitter acetylcholine-enhanced HIF-1α expression in pancreatic cancer cells under hypoxia, leading to the growth of pancreatic cancer organoids. In vitro assays showed that, under hypoxic conditions, acetylcholine caused a concentration-dependent increase in nAChR-α7-mediated HIF-1α expression, enhancing expression of its target genes in pancreatic cancer cells. We further found that acetylcholine increased HIF-1α protein stability in pancreatic cancer cells under hypoxic conditions. This effect was mediated by PDPK1/YAP signaling pathway, as evidenced by the fact that acetylcholine-induced enhancement of HIF-1α expression was blocked by siRNA-mediated knockdown of PDPK1/YAP signaling pathway. Consistent with these findings, an investigation of the relationship between nAChR-α7 and clinicopathological features in pancreatic cancer patients using publicly available datasets showed that high levels of nAChR-α7 are correlated with a poorer prognosis in pancreatic cancer patients. Subsequently, nAChR-α7 specific inhibitor α-bungarotoxin efficiently inhibited the acetylcholine-induced increase of growth of pancreatic cancer organoids under hypoxia. Collectively, these findings identify novel mechanisms by which acetylcholine enhances HIF-1α expression through PDPK1/YAP signaling pathway and provide further evidence that HIF-1α is a potential anticancer target in acetylcholine-associated pancreatic cancer. Citation Format: Yunmi Cho, Eun-Taex Oh, Ha Gyeong Kim, Heon Joo Park. Acetylcholine enhances HIF-1α expression in pancreatic cancer cells under hypoxia through nAchR-α7/PDPK1/YAP signaling pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 196.