Glutaminase inhibition ameliorates cancer-associated fibroblast lipid support of pancreatic cancer cell growth
Abstract Background 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-induce...
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| Format: | Article |
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BMC
2025-08-01
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| Series: | Cancer & Metabolism |
| Online Access: | https://doi.org/10.1186/s40170-025-00389-z |
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| author | Xu Han Laura C. Kim Nicholas P. Lesner Xuanyan Cai Tran Ngoc Van Le M. Celeste Simon |
| author_facet | Xu Han Laura C. Kim Nicholas P. Lesner Xuanyan Cai Tran Ngoc Van Le M. Celeste Simon |
| author_sort | Xu Han |
| collection | DOAJ |
| description | Abstract Background 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. Methods 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. Results 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. Conclusion 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. |
| format | Article |
| id | doaj-art-c6de36bfc7c54a9a94b0e805641d92d3 |
| institution | Kabale University |
| issn | 2049-3002 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Cancer & Metabolism |
| spelling | doaj-art-c6de36bfc7c54a9a94b0e805641d92d32025-08-24T11:47:11ZengBMCCancer & Metabolism2049-30022025-08-0113111610.1186/s40170-025-00389-zGlutaminase inhibition ameliorates cancer-associated fibroblast lipid support of pancreatic cancer cell growthXu Han0Laura C. Kim1Nicholas P. Lesner2Xuanyan Cai3Tran Ngoc Van Le4M. Celeste Simon5Abramson Family Cancer Research Institute, University of PennsylvaniaAbramson Family Cancer Research Institute, University of PennsylvaniaAbramson Family Cancer Research Institute, University of PennsylvaniaAbramson Family Cancer Research Institute, University of PennsylvaniaDepartment of Pathology and Laboratory Medicine, Children’s Hospital of PhiladelphiaAbramson Family Cancer Research Institute, University of PennsylvaniaAbstract Background 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. Methods 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. Results 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. Conclusion 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.https://doi.org/10.1186/s40170-025-00389-z |
| spellingShingle | Xu Han Laura C. Kim Nicholas P. Lesner Xuanyan Cai Tran Ngoc Van Le M. Celeste Simon Glutaminase inhibition ameliorates cancer-associated fibroblast lipid support of pancreatic cancer cell growth Cancer & Metabolism |
| title | Glutaminase inhibition ameliorates cancer-associated fibroblast lipid support of pancreatic cancer cell growth |
| title_full | Glutaminase inhibition ameliorates cancer-associated fibroblast lipid support of pancreatic cancer cell growth |
| title_fullStr | Glutaminase inhibition ameliorates cancer-associated fibroblast lipid support of pancreatic cancer cell growth |
| title_full_unstemmed | Glutaminase inhibition ameliorates cancer-associated fibroblast lipid support of pancreatic cancer cell growth |
| title_short | Glutaminase inhibition ameliorates cancer-associated fibroblast lipid support of pancreatic cancer cell growth |
| title_sort | glutaminase inhibition ameliorates cancer associated fibroblast lipid support of pancreatic cancer cell growth |
| url | https://doi.org/10.1186/s40170-025-00389-z |
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