Grifolin, a potential antitumor natural product from the mushroom Albatrellus confluens, induces cell-cycle arrest in G1 phase via the ERK1/2 pathway

Abstract

Grifolin, a natural product isolated from the mushroom Albatrellus confluens, has been shown to inhibit the growth of some cancer cell lines and induce significant apoptosis. However, the molecular targets and the signaling mechanism underlying the anticancer effect of this compound are not completely understood. Here, we undertook a gene expression profiling study to identify novel targets of grifolin. We found that the effect of grifolin on the human nasopharyngeal carcinoma cell line CNE1 occurs primarily via the ERK1/2 pathway. At high doses, both the ERK1/2 and the ERK5 pathways may be involved in the inhibition. Because inhibition of the ERK1/2 or the ERK5 pathway has been associated with cell-cycle arrest and growth inhibition, we evaluated the cell cycle distribution after grifolin treatment. We found that grifolin significantly caused cell-cycle arrest in G1 phase. To investigate the underlying mechanisms, G1-related proteins were assayed by Western blotting. Following grifolin treatment, a concomitant inhibition of cyclin D1, cyclin E, CDK4 expression, and subsequent reduction in pRB phosphorylation occurred. Meanwhile, grifolin treatment also resulted in a significant upregulation of CKI (p19 INK4D). These results suggest that the inhibition of the ERK1/2 or the ERK5 pathway is responsible for at least part of the induction of cell-cycle arrest in G1 phase by grifolin. These results are significant in that they provide a mechanistic framework for further exploring the use of grifolin as a novel antitumor agent.