Perilaldehyde activates AMP-activated protein kinase to suppress the growth of gastric cancer via induction of autophagy

Background and Aim: Perillaldehyde (PAH), one of the major oil components in Perilla frutescens, is very critical to health maintenance, for a wide range of human chronic diseases, including cancers. AMP-activated protein kinase (AMPK) has been implicated in the activation of autophagy in distinct tissues. This study was designed to explore whether PAH prevents gastric cancer growth and to investigate the molecular mechanism. Methods and Results: In cultured mouse gastric cancer cell line MFCs and human gastric cancer cell lines GC9811-P, PAH activated AMPK by increasing the Thr172 phosphorylation and activity in a time-/concentration-dependent manner. Furthermore, incubation of MFCs with PAH also increased autophagy as determined by monodansylcadaverine (MDC) staining, which was reversed by AMPK inhibitor compound C. PAH further decreased MFCs cell survival, which was abolished by compound C or autophagy inhibitor 3-Methyladenine (3-MA). In vivo studies indicated that 4-week administration of PAH (100mg/kg/day) suppressed the growth of gastric cancer and increased the levels of autophagy-related proteins, including beclin-1, LC3-II, cathepsin, caspase-3, p53, and cathepsin in tumors isolated from the xenograft model of gastric cancer in mice. Moreover, these anticancer effects produced by PAH were abolished by coadministration of compound C or 3-MA in vivo. Conclusions: PAH increases AMPK phosphorylation and activity to induce gastric cancer cell autophagy to inhibit the growth of gastric cancer. In perspective, therapy of PAH should be applied to treat patients with gastric cancer.