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...
Saved in:
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-08-01
|
| Series: | Cancer & Metabolism |
| Online Access: | https://doi.org/10.1186/s40170-025-00389-z |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| Summary: | 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. |
|---|---|
| ISSN: | 2049-3002 |