Scatter factor protects tumor cells against apoptosis caused by TRAIL

Area of Science:

• Oncology
• Molecular Biology
• Cell Biology

Background:

• Scatter factor (SF) and its receptor c-Met are frequently overexpressed in cancers, correlating with poor prognosis.
• Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) shows promise as a tumor-specific agent, but TRAIL resistance limits its clinical use.

Purpose of the Study:

• To investigate how SF protects tumor cells against TRAIL-induced apoptosis.
• To determine if SF-induced TRAIL resistance can be reversed.

Main Methods:

• MTT assays, trypan blue dye exclusion, and apoptosis assays were employed.
• RNA interference, luciferase reporter assays, immunoprecipitation, and western blotting were utilized.
• Cell biological techniques were used to study SF protection in human prostate and breast carcinoma cell lines.

Main Results:

• SF conferred resistance to TRAIL in various human carcinoma cell lines, inhibiting caspase-3 activation, PARP cleavage, and cell death.
• SF-mediated protection required c-Akt but not Src signaling or classical NF-κB activation.
• Protection was blocked by X-linked inhibitor of apoptosis or FLIP knockdown, and SF regulated TRAIL receptor stability via c-Met association.

Conclusions:

• SF protects tumor cells from TRAIL-induced apoptosis through c-Akt activation and modulation of TRAIL receptor stability.
• SF-induced TRAIL resistance can be reversed by inhibiting c-Met or cyclooxygenase 2.
• Findings elucidate mechanisms of TRAIL resistance in SF/c-Met-overexpressing tumors and suggest therapeutic strategies.