Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 08826, South Korea; Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul 08826, South Korea.
Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul 08826, South Korea.
Arch Biochem Biophys. 2020 Aug 15;689:108413. doi: 10.1016/j.abb.2020.108413. Epub 2020 May 27.
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 predicts poor prognosis and a low survival rate in gastric cancer patients. In the present study, we found that resveratrol, one of the representative chemopreventive and anticarcinogenic phytochemicals, directly binds to PIM-1 and thereby inhibits its catalytic activity in human gastric cancer SNU-601 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-independent 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.
莫洛尼鼠白血病病毒（Moloney murine leukemia virus，Mo-MLV）原病毒整合位点（proviral integration site）家族的丝氨酸/苏氨酸特异性激酶包含三个同工型，这些同工型调节癌细胞的增殖、凋亡、代谢、侵袭和转移。在这些同工型中，PIM-1 的激酶活性异常升高，促进了胃癌的进展，并预测胃癌患者预后不良和生存率低。在本研究中，我们发现白藜芦醇（resveratrol）是一种代表性的化学预防和抗癌植物化学物质，可直接与 PIM-1 结合，从而抑制人胃癌 SNU-601 细胞中 PIM-1 的催化活性。这导致促凋亡 Bad 的磷酸化受到抑制，Bad 是 PIM-1 的已知底物。通过使 PIM-1 失活，白藜芦醇还抑制了 SNU-601 细胞的非锚定依赖性生长和增殖。为了了解白藜芦醇与 PIM-1 之间的分子相互作用，我们进行了对接模拟，发现白藜芦醇直接结合在 PIM-1 的 ATP 结合口袋。综上所述，白藜芦醇在胃癌细胞中的促凋亡和抗增殖作用可能是通过抑制 PIM-1 激酶活性介导的，这可能代表其化学预防和抗癌作用的一种新机制。
