Clusterin inhibits apoptosis by interacting with activated Bax

Nat Cell Biol. 7: 278-285 (2005)

Speaker: 曾昱豪                 Date:15:00~16:00, Sep28, 2005

Commentator: 徐麗君 老師        Place: Room 601

Abstract:

    Clusterin is a glycoprotein that has diverse functions including lipid transportation, complement inhibition and regulation of apoptosis. Recent studies reveal that clusterin is over-expressed in several human cancers such as prostate and breast cancers¹. Further investigation shows that suppression of clusterin expression renders human cancer cell sensitive to chemotherapeutic drug-mediated apoptosis. However, the mechanism of sensitivity of clusterin on inhibiting apoptosis in human cancer cells still remains unclear. Here the authors found that intracellular clusterin specifically interacts with activated Bax in mitochondria and prevents Bax oligomerization during chemotherapeutic drugs treatment in HT1080 and PC-3M cells. This interference blocks the release of cytochrome c and caspase activation which contribute to apoptosis². Furthermore, by using an inducible Rat-1/c-MycER cell model system and soft agar assay, they found that clusterin cooperates with c-Myc in oncogenic transformation in vitro. When Rat-1/MycER/Clu cells were subcutaneously injected into nud mice, the expression of clusterin also promotes tumor progression. Finally, the immunostainig data show that clusterin is highly expressed in human metastatic prostate cancer. Knockdown clusterin expression in PC-3M cells renders these cells sensitive to apoptosis. Thus, disrupting the clusterin-Bax interaction may be an attractive strategy for anti-cancer therapy.

References:

1.          Trougakos, I. P. & Gonos, E. S. Clusterin/Apolipoprotein in human aging and cancer. Int. J. Biochem. Cell Biol, 34: 1430-1448 (2002).

2.          Wang, X. The expanding role of mitochondria in apoptosis. Genes Dev, 15: 2922-2933 (2001).

3.          Zhang H. et al Clusterin inhibits apoptosis by interacting with activated Bax. Nat Cell Biol, 7: 909-915 (2005).