Dynasore as a dual modulator of lipid rafts and cell death in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death in the United States and predicted to soon surpass colorectal cancer as the second. The lack of screening tests, advanced stage at diagnosis, and resistance to current treatment regimens underscore the urgent need for novel therapeutic strategies. Targeting lipid rafts, which are specialized membrane microdomains integral to cancer-related processes such as the epithelial-mesenchymal transition, angiogenesis, and metastatic dissemination, offers a promising strategy to combat this deadly disease. As these catalytic platforms regulate signal transduction pathways key to both cell survival and chemoresistance, we investigated the effects of their disruption on PDAC programmed cell death and proliferation using the dynamin inhibitor, Dynasore. In a panel of human PDAC cell lines, Dynasore reduced lipid rafts in the plasma membrane, resulting in increased oxidative and proteotoxic stress which activated the ATR-Chk1 DNA damage response and initiated programmed cell death. Caspase-1 activation led to pyroptosis in the human PDAC cell lines, BxPC-3 and MIA PaCa-2, while Caspase-3 activation induced apoptosis in MIA PaCa-2 and L3.6pl. These cell-specific cell death responses resulted in dose- and time-dependent antiproliferative effects that enhanced gemcitabine cytotoxicity. Our findings suggest that lipid raft inhibition can modulate proliferation, distinct cell death pathways, and treatment response in PDAC. Given the limitations of current therapies, these results emphasize the need for further investigation into lipid raft-targeting agents in combination with chemotherapy to overcome chemoresistance in pancreatic cancer. SIGNIFICANCE: Dynasore exerts potent anti-proliferative and synergistic effects with gemcitabine in vitro by disrupting lipid rafts and differentially inducing programmed cell death, highlighting its potential as a novel therapy in PDAC.