Chemoresistance is a major therapeutic problem and the current knowledge on cellular mechanisms involved is incomplete. In the present study, we have investigated the possible involvement of Fas-associated death domain-like interleukin-1b-converting enzyme (FLICE)-like inhibitory protein (FLIP) in ovarian cancer resistance by comparing chemosensitive (OV2008) and chemoresistant (C13*) ovarian cancer cells treated with cisplatin in vitro, and/ or transfected with FLIP sense cDNA or FLIP small interfering RNA (siRNA) and determining FLIP protein content, cleavage of caspase-8 and caspase-3 and apoptosis. Cisplatin significantly decreased FLIP protein level, induced cleavage of caspase-8 and caspase-3 and apoptosis in a concentration-dependent manner in cisplatinsensitive but not -resistant cells. While overexpression of FLIP-attenuated cisplatin-induced cleavage of caspase-8 and caspase-3 and apoptosis in chemosensitive cells, downregulation of FLIP in chemoresistant cells by siRNA increased apoptosis induced by cisplatin. These results suggest that FLIP plays a significant role in the regulation of apoptosis in human ovarian cancer cells and their sensitivity to cisplatin. This cell survival factor may be an important determinant in chemoresistance in ovarian cancer and may serve as a molecular target for the development of novel therapy for chemoresistant ovarian cancer.

We have previously reported that astrocyte elevated gene-1 (AEG-1) was upregulated in human breast cancer. However, the biological function of AEG-1 in the development and progression of breast cancer remains to be clarified. In this study, we examined the effect of AEG-1 on cell proliferation and found that AEG-1 upregulation was significantly linked to increased Ki67 (Po0.001). Ectopic expression of AEG-1 in MCF-7 and MDA-MB-435 breast cancer cells dramatically enhanced cell proliferation and their ability of anchorage-independent growth, whereas silencing endogenous AEG-1 with shRNAs inhibited cell proliferation and colony-forming ability of the cells on soft agar. Furthermore, these proliferative effects were significantly associated with decreases of p27 Kip1 and p21 Cip1 two key cell-cycle inhibitors. Moreover, we further demonstrated that AEG-1 could downregulate the transcriptional activity of FOXO1 by inducing its phosphorylation through the PI3K/Akt signaling pathway. These observations were further confirmed in clinical human primary breast cancer specimens, in which high-level expression of AEG-1 was inversely correlated with the expression of FOXO1. Taken together, our results provide the first demonstration of a novel mechanism by which AEG-1 induces proliferation of breast cancer cell, and our findings suggest that AEG-1 might play an important role in tumorigenesis of breast cancer.

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