Genistein enhances TRAIL-induced cancer cell death via inactivation of autophagic flux

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a transmembrane cytokine that is a promising anticancer agent as it selectively induces apoptosis in various types of tumor cells. Autophagic flux, which includes the complete process of autophagy, and suppression of autophagic flux has been increasingly recognized as a favorable and novel therapeutic approach for cancer treatment. Here, we showed that genistein, a major isoflavone compound that exerts its anticancer properties by inhibiting tumor cell proliferation, can induce TRAIL-mediated apoptotic cell death in TRAIL-resistant human adenocarcinoma A549 cells. Notably, genistein treatment led to a marked increase in the accumulation of microtubule-associated protein 1 light chain 3 (LC3)-II and p62 protein levels. The combination of genistein and TRAIL increased LC3-II, p62, activated caspase-3 and activated caspase-8 accumulation, confirming the inhibition of autophagic flux. Taken together, our results revealed that genistein enhanced TRAIL-induced tumor cell death in TRAIL-resistant A549 adenocarcinoma cells by inhibiting autophagic flux.