HSP90 inhibition reverses resistance to TRAIL-induced apoptosis in non-small cell lung cancer cells

Resistance to many chemotherapeutic drugs is caused by resistance to induction of apoptosis. TRAIL (TNF-related apoptosis-inducing ligand) selectively triggers apoptosis in cancer cells, but is subject to resistance as well. Combinations may bypass resistance and enhance TRAIL-based therapies. This study investigates whether the HSP90 inhibitor 17-AAG can enhance TRAIL-induced apoptosis in non-small cell lung cancer (NSCLC) cells, either relatively sensitive (H460) or resistant (A549) to TRAIL. Growth inhibition and cell death were assessed using MTT (methyl thiazole tetrazolium) and annexin/propidium iodide assays. Cell cycle analysis was conducted via flow cytometry, and cell death mechanisms were explored with Western blotting. Targeting HSP90 with 17-AAG effectively increased TRAIL-induced apoptosis in H460 cells and reversed resistance to the TRAIL-resistant A549 cells. The significantly enhanced TRAIL-induced apoptosis was mediated through the activation of caspases, particularly caspase-8, while in TRAIL-resistant A549 cells, 17-AAG reinstated apoptosis by cleaving RIPK1, thus preventing RIPK1-dependent survival signaling. Notably, 17-AAG also suppressed Akt activity, a known regulator of TRAIL activity; moreover, inhibition of PI3K by LY294002 sensitized cells to TRAIL-induced apoptosis. These findings suggest that HSP90 inhibitors combined with TRAIL receptor agonists might be of therapeutic value for the treatment of NSCLC.