CYP51A1 drives resistance to pH-dependent cell death in pancreatic cancer
Fangquan Chen, Hu Tang, Changfeng Li, Rui Kang, Daolin Tang, Jiao Liu
Abstract
Disrupted pH homeostasis can precipitate cell death and represents a viable therapeutic target in oncological interventions. Here, we utilize mass spectrometry-based drug analysis, transcriptomic screens, and lipid metabolomics to explore the metabolic mechanisms underlying pH-dependent cell death. We reveal CYP51A1, a gene involved in cholesterol synthesis, as a key suppressor of alkalization-induced cell death in pancreatic cancer cells. Inducing intracellular alkalization by the small molecule JTC801 leads to a decrease in endoplasmic reticulum cholesterol levels, subsequently activating SREBF2, a transcription factor responsible for controlling the expression of genes involved in cholesterol biosynthesis. Specifically, SREBF2-driven upregulation of CYP51A1 prevents cholesterol accumulation within lysosomes, leading to TMEM175-dependent lysosomal proton efflux, ultimately resulting in the inhibition of cell death. In animal models, including xenografts, syngeneic orthotopic, and patient-derived models, the genetic or pharmacological inhibition of CYP51A1 enhances the effectiveness of JTC801 in suppressing pancreatic tumors. These findings demonstrate a role of the CYP51A1-dependent lysosomal pathway in inhibiting alkalization-induced cell death and highlight its potential as a targetable vulnerability in pancreatic cancer. Previously, the opioid analgesic drug JCT801 was reported to induce cell death via disruption of pH homeostasis in pancreatic cancer cells. Here, the authors investigate the metabolic mechanisms underlying JCT801-induced cell death, identifying cholesterol synthesis gene, CYP51A1, as a suppressor of alkalization-induced cell death.