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Resveratrol suppresses gastric cancer cell proliferation and survival through inhibition of PIM-1 kinase activity.
Archives of Biochemistry and Biophysics ( IF 3.8 ) Pub Date : 2020-05-27 , DOI: 10.1016/j.abb.2020.108413
Sujin Kim 1 , Wonki Kim 2 , Do-Hee Kim 3 , Jeong-Hoon Jang 2 , Su-Jung Kim 2 , Sin-Aye Park 4 , Hyunggu Hahn 2 , Byung Woo Han 2 , Hye-Kyung Na 5 , Kyung-Soo Chun 6 , Bu Young Choi 7 , Young-Joon Surh 8
Affiliation  

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.



中文翻译:

白藜芦醇通过抑制PIM-1激酶活性来抑制胃癌细胞的增殖和存活。

莫洛尼氏鼠白血病病毒(PIM)丝氨酸/苏氨酸特异性激酶家族的前病毒整合位点由三种亚型组成,它们调节癌细胞的增殖,凋亡,代谢,侵袭和转移。其中,PIM-1激酶活性的异常升高有助于胃癌的发展,并导致胃癌患者的预后不良和低存活率。在本研究中,我们发现白藜芦醇是代表性的化学预防和抗癌植物化学物质之一,直接与PIM-1结合,从而抑制了其在人胃癌SNU-601胃癌细胞中的催化活性。这导致了凋亡抑制蛋白BIM的已知底物磷酸化的抑制。通过灭活PIM-1,白藜芦醇,还抑制了锚固依赖性SNU-601细胞的生长和增殖。为了了解白藜芦醇和PIM-1之间的分子相互作用,我们进行了对接模拟,发现白藜芦醇在ATP结合口袋处直接与PIM-1结合。总之,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激酶活性来介导的,这可能是其化学预防和抗癌作用的新机制。

更新日期:2020-05-27
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