Clusterin inhibits apoptosis by interacting with activated Bax.
Clusterin is an enigmatic glycoprotein that is overexpressed in several human cancers such as prostate and breast cancers, and squamous cell carcinoma. Because the suppression of clusterin expression renders human cancer cells sensitive to chemotherapeutic drug-mediated apoptosis, it is currently an antisense target in clinical trials for prostate cancer. However, the molecular mechanisms by which clusterin inhibits apoptosis in human cancer cells are unknown. Here we report that intracellular clusterin inhibits apoptosis by interfering with Bax activation in mitochondria. Intriguingly, in contrast to other inhibitors of Bax, clusterin specifically interacts with conformation-altered Bax in response to chemotherapeutic drugs. This interaction impedes Bax oligomerization, which leads to the release of cytochrome c from mitochondria and caspase activation. Moreover, we also find that clusterin inhibits oncogenic c-Myc-mediated apoptosis by interacting with conformation-altered Bax. Clusterin promotes c-Myc-mediated transformation in vitro and tumour progression in vivo. Taken together, our results suggest that the elevated level of clusterin in human cancers may promote oncogenic transformation and tumour progression by interfering with Bax pro-apoptotic activities.
Zhang
Honglai
H
Laboratory of Molecular Signaling and Apoptosis, Department of Biological and Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor, MI 48109-1078, USA.
Kim
Jin Koo
JK
Edwards
Chris A
CA
Xu
Zhaohui
Z
Taichman
Russell
R
Wang
Cun-Yu
CY
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D051152:Clusterin; D045304:Cytochromes c / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D018832:Molecular Chaperones / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism*; D011487:Protein Conformation / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D051381:Rats; D051028:bcl-2-Associated X Protein
D000970:Antineoplastic Agents; C494826:BAX protein, human; C494828:Bax protein, rat; C495242:CLU protein, human; D051152:Clusterin; D006023:Glycoproteins; C489427:MYC protein, human; D018832:Molecular Chaperones; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c; D020169:Caspases