Induction Apoptosis of Erinacine A in Human Colorectal Cancer Cells Involving the Expression of TNFR, Fas, and Fas Ligand via the JNK/p300/p50 Signaling Pathway With Histone Acetylation

Abstract

Erinacine A, which is one of the major bioactive diterpenoid compounds extracted from cultured mycelia of <i>H. erinaceus</i>, displays great antitumorigenic activity. However, the molecular mechanisms underlying erinacine A inducing cancer cell apoptosis in colorectal cancer (CRC) remain unclear. This study found that treatment with erinacine A not only triggers the activation of extrinsic apoptosis pathways (TNFR, Fas, FasL, and caspases) but also suppresses the expression of antiapoptotic molecules Bcl-2 and Bcl-XL <i>via</i> a time-dependent manner in DLD-1 cells. Furthermore, phosphorylation of Jun N-terminus kinase (JNK1/2), NFκB p50, and p300 is involved in erinacine A-induced cancer cell apoptosis. Inhibition of these signaling pathways by kinase inhibitors blocks erinacine A-induced transcriptional activation implicates histone H3K9K14ac (Acetyl Lys9/Lys14) of the TNFR, Fas, and FasL as promoters. Moreover, histochemical and immunohistochemical analyses revealed that erinacine A treatment significantly induced the TNFR, Fas, and FasL levels in the <i>in vivo</i> xenograft mouse model. Together, these results demonstrated an increase in the cellular transcriptional levels of TNFR, Fas, and FasL by erinacine A induction to cell apoptosis <i>via</i> the activation of the JNK, p300, and NFκB p50 signaling modules, thereby providing a new mechanism for erinacine A treatment <i>in vitro</i> and <i>in vivo</i>.