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

Abstract

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.

Attenuation of Lipopolysaccharide-Induced Acute Lung Injury by Hispolon in Mice, Through Regulating the TLR4/PI3K/Akt/mTOR and Keap1/Nrf2/HO-1 Pathways, and Suppressing Oxidative Stress-Mediated ER Stress-Induced Apoptosis and Autophagy

“…Hispolon, with a concentration of 0 to 20 µM (0-4.4 µg/mL), induces the expression of HO-1 protein in BV-2 cells for 24 h under the stimulation of LPS or lipoteichoic acid (LTA), thereby effectively inhibiting the production of iNOS/NO and having no cytotoxicity [29]. Hispolon was also shown to be less cytotoxic to normal cells [39]. Furthermore, hispolon induces apoptosis in acute myeloid leukemia cells and inhibits AML xenograft tumor growth in vivo, where the high dose (10 mg/kg) used is the same as in this study [40].…”

TGF-β and microRNA Interplay in Genitourinary Cancers

“…Unfortunately, that study did not include a statistical analysis of the presented data, so the conclusions remain elusive [334]. TGF-β is also a target of hispolon (6 -(3,4-dihydroxyphenyl)-4-hydroxyhexa-3,5-dien-2-one), HPL), a compound isolated from Phellinus linteus, exerting anticancer properties against multiple tumor types, including cancers of the cervix, colon, and kidney [335,336], as well as melanoma [337]. Hong et al showed that HPL attenuates TGF-β-induced EMT of bladder cancer cells, resulting in reduced migration and invasion [338].…”

Hispolon as an inhibitor of TGF-β-induced epithelial-mesenchymal transition in human epithelial cancer cells by co-regulation of TGF-β-Snail/Twist axis

“…However, HPL has not been associated with cancer metastasis via the EMT, although its strong antitumor effects have been reported (31). To the best of our knowledge, this is the first study to demonstrate that the anti-metastatic effects of HPL are associated with the EMT in cultured human cancer cells.…”