Subcellular localization of X-linked inhibitor of apoptosis protein (XIAP) in cancer: Does that matter?

X-linked inhibitor of apoptosis protein (XIAP) finely tunes the balance between survival and death to control homeostasis. XIAP is found aberrantly expressed in cancer, which has been shown to promote resistance to therapy-induced apoptosis and confer poor outcome. Despite its predominant cytoplasmic localization in human tissues, growing evidence implicates the expression of XIAP in other subcellular compartments in sustaining cancer hallmarks. Herein, we review our current knowledge on the prognostic role of XIAP localization and discuss molecular mechanisms underlying differential biological functions played in each compartment. The comprehension of XIAP subcellular shuttling and functional dynamics might provide the rationale for future anticancer therapeutics.

Forkhead box K2 modulates epirubicin and paclitaxel sensitivity through FOXO3a in breast cancer.

The forkhead transcription factor FOXK2 has recently been implicated in cancer cell proliferation and survival, but a role in cancer chemotherapeutic drug resistance has hitherto not been explored. Here we demonstrate that FOXK2 has a central role in mediating the cytotoxic drug response in breast cancer. Clonogenic and cell viability assays showed that enhanced FOXK2 expression sensitizes MCF-7 breast cancer cells to paclitaxel or epirubicin treatment, whereas FOXK2 depletion by small interfering RNAs (siRNAs) confers drug resistance. Our data also showed that the activation of the tumour suppressor FOXO3a by paclitaxel and epirubicin is mediated through the induction of FOXK2, as depletion of FOXK2 by siRNA limits the induction of FOXO3a by these drugs in MCF-7 cells. Chromatin immunoprecipitation (ChIP) analysis showed that in response to drug treatment, FOXK2 accumulates and binds to the proximal FOXO3a promoter region in MCF-7 cells. Furthermore, we also uncovered that FOXK2 is deregulated and, therefore, can express at high levels in the nucleus of both the paclitaxel and epirubicin drug-resistant MCF-7 cells. Our results showed that ectopically overexpressed FOXK2 accumulates in the nuclei of drug-resistant MCF-7 cells but failed to be recruited to target genes, including FOXO3a. Crucially, we found that FOXO3a is required for the anti-proliferative and epirubicin-induced cytotoxic function of FOXK2 in MCF-7 cells by sulphorhodamine and clonogenic assays. The physiological importance of the regulation of FOXO3a by FOXK2 is further confirmed by the significant correlations between FOXO3a and FOXK2 expression in breast carcinoma patient samples. Further survival analysis also reveals that high nuclear FOXK2 expression significantly associates with poorer clinical outcome, particularly in patients who have received conventional chemotherapy, consistent with our finding that FOXK2 is deregulated in drug-resistant cells. In summary, our results suggest that paclitaxel and epirubicin target the FOXK2 to modulate their cytotoxicity and deregulated FOXK2 confers drug resistance.