Wu William Ka Kei, Wu Ya Chun, Yu Le, Li Zhi Jie, Sung Joseph Jao Yiu, Cho Chi Hin
Department of Pharmacology, Basic Medical Sciences Building, The Chinese University of Hong Kong, Shatin, NT, Hong Kong, China.
Biochem Biophys Res Commun. 2008 Sep 19;374(2):258-63. doi: 10.1016/j.bbrc.2008.07.031. Epub 2008 Jul 16.
The ubiquitin-proteasome system (UPS) and lysosome-dependent macroautophagy (autophagy) are two major intracellular pathways for protein degradation. Blockade of UPS by proteasome inhibitors has been shown to activate autophagy. Recent evidence also suggests that proteasome inhibitors may inhibit cancer growth. In this study, the effect of a proteasome inhibitor MG-132 on the proliferation and autophagy of cultured colon cancer cells (HT-29) was elucidated. Results showed that MG-132 inhibited HT-29 cell proliferation and induced G(2)/M cell cycle arrest which was associated with the formation of LC3(+) autophagic vacuoles and the accumulation of acidic vesicular organelles. MG-132 also increased the protein expression of LC3-I and -II in a time-dependent manner. In this connection, 3-methyladenine, a Class III phosphoinositide 3-kinase inhibitor, significantly abolished the formation of LC3(+) autophagic vacuoles and the expression of LC3-II but not LC3-I induced by MG-132. Taken together, this study demonstrates that inhibition of proteasome in colon cancer cells lowers cell proliferation and activates autophagy. This discovery may shed a new light on the novel function of proteasome in the regulation of autophagy and proliferation in colon cancer cells.
泛素-蛋白酶体系统（UPS）和溶酶体依赖性巨自噬（自噬）是蛋白质降解的两条主要细胞内途径。蛋白酶体抑制剂对UPS的阻断已被证明可激活自噬。最近的证据还表明，蛋白酶体抑制剂可能抑制癌症生长。在本研究中，阐明了蛋白酶体抑制剂MG-132对培养的结肠癌细胞（HT-29）增殖和自噬的影响。结果显示，MG-132抑制HT-29细胞增殖并诱导G(2)/M期细胞周期阻滞，这与LC3(+)自噬泡的形成和酸性囊泡细胞器的积累有关。MG-132还以时间依赖性方式增加LC3-I和-II的蛋白表达。在此方面，III类磷酸肌醇3-激酶抑制剂3-甲基腺嘌呤显著消除了MG-132诱导的LC3(+)自噬泡的形成和LC3-II的表达，但未消除LC3-I的表达。综上所述，本研究表明，结肠癌细胞中蛋白酶体的抑制降低了细胞增殖并激活了自噬。这一发现可能为蛋白酶体在调节结肠癌细胞自噬和增殖中的新功能提供新的线索。
