Resveratrol Suppresses Gastric Cancer Cell Growth and Proliferation through Inhibition PIM-1 Kinase Activity

Abstract

The PIM kinases are serine/threonine kinases composed of three members PIM-1, PIM-2 and PIM-3, and regulate cell cycle progression, apoptosis, cell metabolism, invasion and metastasis. Among these, abnormally elevated kinase activity of PIM-1 contributes to the progression of gastric cancer which is responsible for poor prognosis and low survival. In the present study, a kinase assay was conducted to identify a new molecular target of resveratrol, one of the representative chemopreventive and anticarcinogenic phytochemicals. PIM-1 and PIM-2 kinase activities were markedly inhibited by a relatively low concentration of resveratrol. Using SNU gastric cancer cell lines which were established from Korean gastric cancer patients, a PIM-1 overexpressing cancer cell line (SNU-601) was selected. In a SNU-601 gastric cancer cell line, resveratrol physically binds to the PIM-1 kinase and reduces phosphorylation of Bad which is a well-known substrate of PIM-1. Moreover, resveratrol barely exerts inhibitory effects on the transcription and expression of PIM-1. Resveratrol by inhibiting PIM-1 activity suppresses anchorage-dependent and -independent growth and neoplastic transformation of SNU-601 cell. Likewise, proliferative and colony forming ability of SNU-601 cells were prominently reduced by knockdown of PIM-1, and the proportion of apoptotic cells was also increased. In conclusion, the inhibitory effects of resveratrol on gastric cancer cell growth and proliferation are likely to be mediated through suppression of PIM-1 kinase activity.