Hispolon from Phellinus linteus induces apoptosis and sensitizes human cancer cells to the tumor necrosis factor-related apoptosis-inducing ligand through upregulation of death receptors

The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent anticancer agent possessing the ability to induce apoptosis in various cancer cells but not in non-malignant cells. However, certain type of cancer cells are resistant to TRAIL-induced apoptosis and some acquire resistance after the first treatment. So development of an agent that can reduce or avoid resistance in TRAIL-induced apoptosis has garnered significant attention. The present study evaluated the anticancer potential of hispolon in TRAIL-induced apoptosis and indicated hispolon can sensitize cancer cells to TRAIL. As the mechanism of action was examined, hispolon was found to activate caspase-3, caspase-8 and caspase-9, while downregulating the expression of cell survival proteins such as cFLIP, Bcl-2 and Bcl-xL and upregulating the expression of Bax and truncated Bid. We also found hispolon induced death receptors in a non-cell type-specific manner. Upregulation of death receptors by hispolon was found to be p53-independent but linked to the induction of CAAT enhancer binding protein homologous protein (CHOP). Overall, hispolon was demonstrated to potentiate the apoptotic effects of TRAIL through downregulation of anti-apoptotic proteins and upregulation of death receptors linked with CHOP and pERK elevation.