Resveratrol suppresses gastric cancer cell proliferation and survival through inhibition PIM-1 kinase activity.

The proviral integration site for Moloney murine leukemia virus (PIM) family of serine/threonine-specific kinases consist of three isoforms, that regulate proliferation, apoptosis, metabolism, invasion and metastasis of cancer cells. Among these, abnormally elevated kinase activity of PIM-1 contributes to the progression of gastric cancer and responsible for poor prognosis and low survival rate in gastric cancer patients. In the present study, we found that resveratrol, one of the representative chemopreventive and anticarcinogenic phytochemical, directly binds to PIM-1 and thereby inhibits its catalytic activity in human gastric cancer SNU-601 gastric cancer cells. This resulted in suppression of phosphorylation of the proapoptotic Bad a known substrate of PIM-1. Resveratrol, by inactivating PIM-1, also inhibited anchorage-dependent growth and proliferation of SNU-601 cells. To understand the molecular interaction between resveratrol and PIM-1, we conducted docking simulation and found that resveratrol directly binds to the PIM-1 at the ATP-binding pocket. In conclusion, the proapototic and anti-proliferative effects of resveratrol in gastric cancer cells are likely to be mediated through suppression of PIM-1 kinase activity, which may represent a novel mechanism underlying its chemopreventive and anticarcinogenic actions.