Bexarotene-induced cell death in ovarian cancer cells through Caspase-4-gasdermin E mediated pyroptosis

Area of Science:

• Oncology
• Molecular Biology
• Cell Biology

Background:

• Bexarotene is an established anticancer agent for cutaneous T-cell lymphoma.
• Retinoid X receptor (RXR) activation is a key mechanism of bexarotene's action.
• The therapeutic potential of bexarotene in ovarian cancer remains largely unexplored.

Purpose of the Study:

• To investigate the in vitro anticancer effects of bexarotene in ovarian cancer.
• To elucidate the underlying molecular mechanisms of bexarotene-induced cell death in ovarian cancer.
• To evaluate bexarotene's impact on cell proliferation, cell cycle, and specific cell death pathways.

Main Methods:

• Ovarian cancer cell lines (ES2 and NIH:OVACAR3) were treated with varying concentrations of bexarotene (0-20 µM).
• Cell proliferation was assessed via cell counting and lactate dehydrogenase (LDH) cytotoxicity assays.
• Gene expression (CDKN1A), protein levels, cell cycle distribution, apoptosis, and pyroptosis markers (caspase-4, GSDME) were analyzed.

Main Results:

• Bexarotene significantly reduced ovarian cancer cell proliferation across all tested concentrations.
• Higher bexarotene concentrations (>10 µM) led to increased LDH release, indicating cell membrane damage.
• Treatment with 10 µM bexarotene induced cell cycle arrest (increased sub-G1 population) and upregulated CDKN1A.
• Bexarotene triggered pyroptosis, evidenced by caspase-4 and GSDME activation, without activating caspase-3 in ES2 cells.

Conclusions:

• Bexarotene demonstrates significant anticancer activity against ovarian cancer cell lines in vitro.
• The primary mechanism of bexarotene-induced cell death involves caspase-4-mediated pyroptosis.
• Bexarotene holds promise as a potential novel therapeutic agent for ovarian cancer treatment.