FAU regulates carboplatin resistance in ovarian cancer

Abstract

The development of chemotherapy resistance by cancer cells is complex, using different mechanisms and pathways. The gene FAU (Finkel-Biskis-Reilly murine sarcoma virus (FBR-MuSV)-associated ubiquitously expressed gene) was identified through functional expression cloning and previous data have shown that overexpression enhances apoptosis in several cell types. We demonstrate that the expression of FAU was reduced in the A2780cis (cisplatin resistant subclone of A2780) cell line compared with the A2780 ovarian cancer cell line, and was directly related to the cell line's sensitivity to carboplatin. Downregulation of FAU in the A2780 cell line by transfection with two predesigned short-interfering RNAs (siRNAs) to FAU resulted in a significant increase in resistance to carboplatin-induced cell death. Downregulation resulted in increased cell viability and reduced apoptosis after 72 hr of drug treatment compared with the negative controls (Kruskal-Wallis P = 0.0002). Transfection of the A2780cis cell line with the pcDNA3 plasmid containing FAU was associated with increased sensitivity to carboplatin-induced apoptosis, with decreased cell viability and increased apoptosis (Mann Whitney P < 0.0001). The expression of FAU was examined by quantitative real-time reverse transcriptase polymerase chain reaction in normal and malignant ovarian tissue. A significant reduction in the expression of FAU was seen in the malignant compared with normal ovarian samples (Kruskal-Wallis P = 0.0261). These data support a role for FAU in the regulation of platinum-resistance in ovarian cancer. Further research is needed into the apoptotic pathway containing FAU to investigate the potential for targeted therapies to increase or restore the platinum sensitivity of ovarian cancer.

Hc-fau, a novel gene regulating diapause in the nematode parasite Haemonchus contortus

“…Expression of fox increases the transforming capability and tumorigenicity of the virus, presumably by inactivating fau expression in the mouse (Michiels et al, 1993). Expression of fau is down-regulated in both breast cancer (Pickard et al, 2009) and ovarian cancer (Moss et al, 2010). A sequence antisense to fau is able to inhibit apoptosis (AP) induced by dexamethasone, UV or cisplatin in W7.2c cells (Mourtada-Maarabouni et al, 2004).…”

Candidate tumour suppressor Fau regulates apoptosis in human cells: An essential role for Bcl-G

“…It can be further postulated that FUBI-mediated modification of Bcl-G forms part of the molecular mechanism by which FAU regulates apoptosis. Indeed, recent studies in our laboratory have shown that FAU gene expression is down-regulated in human breast, prostate and ovarian tumours [13][14][15] and that siRNA-mediated silencing of FAU and BCL-L14…”

FAU (Finkel-Biskis-Reilly murine sarcoma virus (FBR-MuSV) ubiquitously expressed)

“…Further work in human T-cell lines and the epithelial cell line, 293T/17, has confirmed that ectopic FAU expression increases basal apoptosis, and that siRNA-mediated silencing of FAU attenuates apoptosis in response to ultraviolet-C irradiation (Pickard et al, 2011). FAU also regulates apoptosis in other human epithelial cell lines derived from breast (Pickard et al, 2009), ovarian (Moss et al, 2010) and prostate tumours (see 'Implicated in'). FUBI has been shown to covalently modify Bcl-G (a pro-apoptotic member of the Bcl-2 family) in mouse cells (Nakamura and Tanigawa, 2003), and it is feasible therefore, that FAU regulates apoptosis via Bcl-G.…”

“…Note A reduction in FAU gene expression has been reported for malignant versus normal ovarian tissue, and for Type I ovarian tumours (typically include mucinous, endometrioid, clear cell, and low-grade serous cancers), in particular (Moss et al, 2010). Over-expression of FAU in a cisplatin-resistant ovarian cancer cell subline, A2780cis, resulted in increased sensitivity to carboplatin-induced apoptosis (Moss et al, 2010).…”

“…Over-expression of FAU in a cisplatin-resistant ovarian cancer cell subline, A2780cis, resulted in increased sensitivity to carboplatin-induced apoptosis (Moss et al, 2010). Conversely, down-regulation of FAU in the A2780 parental cell line resulted in increased resistance to carboplatin-induced apoptosis (Moss et al, 2010).…”