Grifolin induces apoptosis via inhibition of PI3K/AKT signalling pathway in human osteosarcoma cells

Abstract

Grifolin, a natural biologically active substance isolated from the edible bodies of the mushroom Albatrellus confluens, has been shown to inhibit proliferation and induce apoptosis in several cancer cell lines. But the mechanisms remain poorly understood. In this study, we investigated the apoptosis-inducing effects and the mechanisms of grifolin on human osteosarcoma cells. Our results demonstrated that grifolin induced concentration- and time-dependent suppression of proliferation and induction of apoptosis in U2OS and MG63 osteosarcoma cell lines. Grifolin induced the release of cytochrome c accompanied by activation of caspase-9, caspase-3 and cleavage of poly (ADP-ribose) polymerase (PARP). In addition, z-VAD-fmk, a universal inhibitor of caspases, prevented caspase-3 activation and PARP cleavage and inhibted grifolin-induced cell growth inhibition. Furthermore, grifolin treatment resulted in a reduction in level of phosphorylated AKT, FOXO transcription factor, and glycogen synthase kinase 3 (GSK3). Knockdown of GSK3 with siRNA inhibited the apoptotic effects of grifolin. On the other hand, grifolin treatment down-regulated the expression of the inhibitor of apoptosis protein(IAP) in both osteosarcoma cells. Taken together, our results suggested that grifolin is able to suppress the phosphorylation of Akt and its substrates FOXO transcription factor and GSK3 in osteosarcoma cells causing the suppression of proliferation and induction of mitochondria- and caspase-dependent apoptosis.

Grifolin induces autophagic cell death by inhibiting the Akt/mTOR/S6K pathway in human ovarian cancer cells

“…This is the first study on the role of grifolin in inducing autophagy in ovarian cancer. A previous study showed that grifolin induced cell cycle arrest in G1 phase via the ERK1/2 pathway (6), and also induced apoptosis through the Bax/Bcl-2 and caspase-3/-9 families via inhibition of PI3K/Akt signalling pathway in human osteosarcoma cells (8). In addition, it has been reported that grifolin upregulated death-associated protein kinase 1 DAPK1 via p53 and mediated G1 phase arrest in nasopharyngeal carcinoma cells (4,7).…”

“…Grifolin (2-trans, trans-farnesyl-5-methylresorcinol), a secondary metabolite extracted from the mushroom Albatrellus confluens, is an antibiotic belonging to basidiomycota (2,3). Several mechanisms have been reported, including inhibition of G1 phase cell cycle (4-6), promotion of apoptosis proteins (7,8) suppression of cell metastasis (9) which have been proposed to explain grifolin's antitumor effects. However, the other mechanisms of the drug's antitumor effects have remained unclear.…”

Forkhead box-O transcription factor: critical conductors of cancer's fate

“…Recent approaches to suppress tumour growth by inducing cell cycle arrest and apoptosis in a FOXOdependent manner have shown promising results (Sunters et al 2003, Hussain et al 2006, Dong et al 2007, Jin et al 2007a. Interventions on different regulatory stages of FOXO function resulting in either restoration or augmentation of FOXO function seem especially useful for drug-targeting:…”

FOXO factors and breast cancer: outfoxing endocrine resistance

“…For instance, treatment of chronic myeloid leukaemia with the pan tyrosine kinase inhibitor imatinib (Gleevec), inhibited PI3K-AKT signaling, and effectively restored FOXO3A transcriptional activity (Fernandez de Mattos et al 2004, Essafi et al 2005. A similar effect is also observed in osteosarcoma cells treated with the PI3K-AKT inhibitor Grifolin (Jin et al 2007).…”