GSK1059615 kills head and neck squamous cell carcinoma cells possibly via activating mitochondrial programmed...

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Head and neck squamous cell carcinoma (HNSCC) is a prevalent cancer with limited therapeutic options.
• The phosphoinositide 3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) pathway is frequently dysregulated in HNSCC, making it a promising therapeutic target.

Purpose of the Study:

• To evaluate the anti-cancer activity of GSK1059615, a novel dual inhibitor of PI3K and mTOR, against HNSCC cells.
• To elucidate the mechanism of cell death induced by GSK1059615 in HNSCC.

Main Methods:

• GSK1059615 was used to treat established and primary human HNSCC cell lines.
• PI3K-AKT-mTOR pathway activation was assessed.
• Apoptosis and programmed necrosis were evaluated using various assays, including mitochondrial depolarization, cyclophilin-D association, and lactate dehydrogenase (LDH) release.
• In vivo efficacy was tested using SCC-9 tumor xenografts in nude mice.

Main Results:

• GSK1059615 inhibited HNSCC cell survival, proliferation, and PI3K-AKT-mTOR pathway activation.
• GSK1059615 induced programmed necrosis, characterized by mitochondrial depolarization and LDH release, rather than apoptosis.
• Inhibition of the mitochondrial permeability transition pore (mPTP) or cyclophilin-D attenuated GSK1059615-induced cell death.
• GSK1059615 suppressed tumor growth in vivo, an effect diminished by co-administration with cyclosporin A.

Conclusions:

• GSK1059615 exhibits potent anti-HNSCC activity by inhibiting the PI3K-AKT-mTOR pathway.
• The compound preferentially induces programmed necrosis in HNSCC cells, suggesting a novel cell death mechanism.
• Targeting the PI3K-AKT-mTOR pathway with GSK1059615 represents a potential therapeutic strategy for HNSCC.