Institute of Digestive Diseases, LKS Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, NT, Hong Kong, P.R. China.
Autophagy. 2010 Feb;6(2):228-38. doi: 10.4161/auto.6.2.11042. Epub 2010 Feb 24.
The ubiquitin-proteasome system and macroautophagy are two complementary pathways for protein degradation. Emerging evidence suggests that proteasome inhibition might be a promising approach for the treatment of cancer. In this study, we show that proteasome inhibitor MG-132 suppressed gastric cancer cell proliferation and induced macroautophagy. The induction of macroautophagy was evidenced by the formation of LC3(+) autophagosomes and the accumulation of acidic vesicular organelles and autolysosomes and was accompanied by the suppression of mammalian target of rapamycin complex 1 activity. Abolition of macroautophagy by knockdown of Class III phosphatidylinositol-3 kinase Vps34 or ATG5/7 sensitized gastric cancer cells to the antiproliferative effect of MG-132 by promoting G(2)/M cell cycle arrest. In addition, MG-132 increased ERK phosphorylation whose inhibition by MEK inhibitor significantly enhanced the antiproliferative effect of proteasome inhibition. To conclude, this study demonstrates that macroautophagy and ERK phosphorylation serve as protective mechanisms to counteract the antiproliferative effect of proteasome inhibition. This discovery may have implications for the application of proteasome-directed therapy for the treatment of cancer.
泛素-蛋白酶体系统和巨自噬是两种蛋白质降解的互补途径。新出现的证据表明，蛋白酶体抑制可能是治疗癌症的一种很有前途的方法。在这项研究中，我们表明蛋白酶体抑制剂 MG-132 抑制了胃癌细胞的增殖并诱导了巨自噬。自噬的诱导通过 LC3(+)自噬体的形成和酸性囊泡细胞器和自溶体的积累得到证明，并伴随着哺乳动物雷帕霉素靶蛋白复合物 1 活性的抑制。通过敲低 Class III 磷酸肌醇-3 激酶 Vps34 或 ATG5/7 来消除巨自噬，使胃癌细胞对 MG-132 的增殖抑制作用敏感，通过促进 G2/M 细胞周期阻滞来实现。此外，MG-132 增加了 ERK 磷酸化，MEK 抑制剂对其的抑制显著增强了蛋白酶体抑制的增殖抑制作用。总之，本研究表明，巨自噬和 ERK 磷酸化作为保护性机制，对抗蛋白酶体抑制的增殖抑制作用。这一发现可能对蛋白酶体定向治疗癌症的应用具有重要意义。
