Clusterin; survival; apoptosis; Prostate; Cancer; Akt pathway; castration resistance; Proteomic; Tet On system; inducible cell line; Mat LyLu
Abstract :
[en] Prostate cancer is the second leading cause of cancer death in men. Although
androgen ablation remains the most effective management option, most patients with
advanced disease progress to castration resistant prostate cancer (CRPC), within two
years of treatment. This results, in part, from the increase in the anti-apoptotic
molecules expression following androgen withdrawal. Among the proteins involved in
this phenomenon, clusterin, also known as testosterone repressed message-2 (TRPM-
2), which exists in two forms: a pro-apoptotic nuclear form (nClU) and a secreted
survival factor (sClU).
In our study we investigated the role of the secreted form of clusterin in preventing
cells from TNFα-induced apoptosis. For this, we first generated a sCLU inducible stable
prostatic cancer MLL rat cell line by using the Tet-On gene expression system. With this
model we revealed a new mechanism by which sCLU promotes survival in androgenindependent
prostate cancer cells, implicating its receptor megalin and the Akt
survival pathway.
By applying a comparative proteomic analysis in the androgen-independent epithelial
cell line MLLTet-sClu induced to overexpress sClu or non induced control-cells, we
identified five proteins known to play a role in cancer. These proteins candidates are
heat shock proteins Hsp90 and Hsp70, osteopontin (bone sialoprotein, OPN),
proliferating cell nuclear antigen (PCNA) and ADP-ribosylation factor 1 (Arf1).
Altogether, our data provide new mechanistic insight in sCLU dependent activation of
the major survival pathway upregulated in refractory prostate cancer. The
identification of the new sCLU protein targets open new avenues for more research to
elucidate the significance of clusterin in prostate cancer progression and resistance to
therapy.
