{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Han X"],"funding":["NCI NIH HHS"],"pagination":["38"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC12366226"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["13(1)"],"pubmed_abstract":["<h4>Background</h4>Lipid homeostasis is critical for pancreatic adenocarcinoma (PDAC) cell survival under hypoxic and nutrient-deprived conditions. Hypoxia inhibits unsaturated lipid biosynthesis, compelling cancer cells to depend on exogenous unsaturated lipids to counteract saturated lipid-induced toxicity. Our previous work revealed that cancer-associated fibroblasts (CAFs) secrete unsaturated lipids, primarily lysophosphatidylcholines (LPCs), to alleviate lipotoxic stress in PDAC cells. Here, we conducted a drug screen to identify compounds that bypass the rescue effect of exogenous LPCs on cancer cell survival under stress.<h4>Methods</h4>We employed high-throughput screening of a bioactive chemical library with 3,336 compounds, including FDA-approved drugs and drug-like molecules against defined molecular targets. Two assays were performed: a cytotoxicity assay to exclude indiscriminately toxic compounds at 1 μM and an LPC crosstalk inhibition assay to identify compounds that selectively reduce cancer cell viability in the presence of LPCs under stress conditions.<h4>Results</h4>CB-839, a glutaminase inhibitor, was identified as the most effective compound, selectively inhibiting the LPC-mediated rescue of PDAC cell viability effect without intrinsic cytotoxicity. Mechanistic studies revealed that CB-839 induces cell death by activating the pro-apoptotic ATF4/CHOP pathway, reducing antioxidant production, and increasing reactive oxygen species (ROS). While CB-839 showed limited efficacy against PDAC tumor cells alone in vivo, it modestly inhibited tumor growth in a PDAC-CAF co-implanted subcutaneous mouse model, highlighting its potential to disrupt CAF-mediated nutrient support. Additionally, glutamine antagonists showed more potent tumor-suppressive effects than CB-839.<h4>Conclusion</h4>Our findings emphasize the importance of glutamine metabolism inhibition in suppressing tumor growth and disrupting CAF-mediated crosstalk. We further underscore the potential of glutamine antagonist prodrugs as a strategy to target metabolic vulnerabilities in PDAC."],"journal":["Cancer & metabolism"],"pubmed_title":["Glutaminase inhibition ameliorates cancer-associated fibroblast lipid support of pancreatic cancer cell growth."],"pmcid":["PMC12366226"],"funding_grant_id":["T32 CA009140","R01 CA276512","R35 CA220483"],"pubmed_authors":["Van Le TN","Han X","Kim LC","Lesner NP","Cai X","Simon MC"],"additional_accession":[]},"is_claimable":false,"name":"Glutaminase inhibition ameliorates cancer-associated fibroblast lipid support of pancreatic cancer cell growth.","description":"<h4>Background</h4>Lipid homeostasis is critical for pancreatic adenocarcinoma (PDAC) cell survival under hypoxic and nutrient-deprived conditions. Hypoxia inhibits unsaturated lipid biosynthesis, compelling cancer cells to depend on exogenous unsaturated lipids to counteract saturated lipid-induced toxicity. Our previous work revealed that cancer-associated fibroblasts (CAFs) secrete unsaturated lipids, primarily lysophosphatidylcholines (LPCs), to alleviate lipotoxic stress in PDAC cells. Here, we conducted a drug screen to identify compounds that bypass the rescue effect of exogenous LPCs on cancer cell survival under stress.<h4>Methods</h4>We employed high-throughput screening of a bioactive chemical library with 3,336 compounds, including FDA-approved drugs and drug-like molecules against defined molecular targets. Two assays were performed: a cytotoxicity assay to exclude indiscriminately toxic compounds at 1 μM and an LPC crosstalk inhibition assay to identify compounds that selectively reduce cancer cell viability in the presence of LPCs under stress conditions.<h4>Results</h4>CB-839, a glutaminase inhibitor, was identified as the most effective compound, selectively inhibiting the LPC-mediated rescue of PDAC cell viability effect without intrinsic cytotoxicity. Mechanistic studies revealed that CB-839 induces cell death by activating the pro-apoptotic ATF4/CHOP pathway, reducing antioxidant production, and increasing reactive oxygen species (ROS). While CB-839 showed limited efficacy against PDAC tumor cells alone in vivo, it modestly inhibited tumor growth in a PDAC-CAF co-implanted subcutaneous mouse model, highlighting its potential to disrupt CAF-mediated nutrient support. Additionally, glutamine antagonists showed more potent tumor-suppressive effects than CB-839.<h4>Conclusion</h4>Our findings emphasize the importance of glutamine metabolism inhibition in suppressing tumor growth and disrupting CAF-mediated crosstalk. We further underscore the potential of glutamine antagonist prodrugs as a strategy to target metabolic vulnerabilities in PDAC.","dates":{"release":"2025-01-01T00:00:00Z","publication":"2025 Aug","modification":"2026-05-29T15:04:10.932Z","creation":"2026-04-08T05:11:29.42Z"},"accession":"S-EPMC12366226","cross_references":{"pubmed":["40835956"],"doi":["10.1186/s40170-025-00389-z"]}}