Abstract A114: HSF1 supports LDLR expression and LDL-cholesterol uptake in pancreatic ductal adenocarcinoma
Ahmad Hegazi, Rejina Shrestha, Deep B. Patel, Kuo-Hui SuAbstract
Introduction:
Pancreatic ductal adenocarcinoma (PDAC) is a highly adaptive malignancy that survives within a harsh, nutrient-depleted microenvironment. Within this environment, PDAC cells rely on cholesterol metabolism to support membrane synthesis and tumor growth. Low-density lipoprotein (LDL) cholesterol is a key extracellular cholesterol source, and increased LDL receptor (LDLR) expression has been associated with more aggressive disease and poorer outcomes in PDAC. Heat shock factor 1 (HSF1), a central regulator of cellular stress responses, is similarly overexpressed in aggressive PDAC and has been associated with cholesterol homeostasis, particularly de novo cholesterol synthesis. However, whether HSF1 also contributes to cholesterol homeostasis by regulating LDLR expression and LDL-cholesterol uptake remains unclear. We hypothesized that HSF1 supports cholesterol homeostasis in part through regulation of LDLR expression and LDL-cholesterol uptake.
Methods:
HSF1 was knocked down in PANC-1 and MIA PaCa-2 PDAC cells using siRNA. Intracellular neutral lipid accumulation was measured using Nile Red staining. LDL uptake was measured using fluorescently labeled DiI-LDL. HSF1 and LDLR protein expression were measured by immunoblotting, and mRNA expression of LDLR and downstream HSF1 transcript HSP72 were measured by RT-qPCR. Berberine and HSF1 inhibitor KRIBB11 were used to assess the expression level of HSF1 activity, HSPs mRNA and LDLR. Cell viability was measured using the Cell Counting Kit-8 assay.
Results:
HSF1 knockdown reduced LDLR protein expression and LDL-cholesterol uptake in both PANC-1 and MIA PaCa-2 cells. Nile Red staining was correspondingly reduced following HSF1 knockdown, consistent with diminished neutral lipid accumulation. Berberine or HSF1 inhibitor treatment reduced HSP72 mRNA, LDLR mRNA, LDLR protein expression, and decreased PDAC cell viability.
Conclusion:
These findings identify HSF1 as a novel regulator of LDLR-mediated cholesterol uptake in PDAC. Berberine-induced HSPs reduction further suggests that pharmacologic disruption of the HSF1-LDLR axis may represent a potential strategy to target cholesterol-dependent vulnerabilities in pancreatic cancer.
Citation Format:
Ahmad Hegazi, Rejina Shrestha, Deep B. Patel, Kuo-Hui Su. HSF1 supports LDLR expression and LDL-cholesterol uptake in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Therapeutic Development; 2026 Sep 25-28; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_2):Abstract nr A114.