PI3K/mTOR Inhibitor Induces Context-Dependent Apoptosis and Methuosis in Cancer Cells.

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Targeting the PI3K/mTOR pathway is crucial for cancer therapy.
• Apoptosis resistance limits the efficacy of current cancer treatments.
• Investigating novel cell death mechanisms beyond apoptosis is essential.

Purpose of the Study:

• To investigate the dual PI3K/mTOR inhibitor YYN-37.
• To explore YYN-37's capacity to induce context-dependent cell death, including methuosis.
• To evaluate the role of VPS34 in YYN-37-induced cell death.

Main Methods:

• Utilized HCT-116 and SJSA-1 cancer cell lines.
• Performed cell viability assays, Western blot, and fluorescent tracers.
• Employed pathway-specific inhibitors, VPS34 knockdown, proteomic profiling, and in vivo xenograft models.

Main Results:

• YYN-37 induced apoptosis in HCT-116 cells and VPS34-dependent methuosis (cytoplasmic vacuolization) in SJSA-1 cells.
• YYN-37 directly inhibited VPS34 (IC50 = 2.73 nM).
• YYN-37 demonstrated significant anti-tumor efficacy (72.71% growth inhibition) in vivo.

Conclusions:

• YYN-37 exhibits potent, context-dependent anti-tumor effects via apoptosis or methuosis.
• Methuosis induction is a viable therapeutic strategy for apoptosis-resistant cancers.
• VPS34 inhibition represents a promising mechanism for cancer therapy.