Abstract
It has been reported that chemotherapy resistance mainly contributed to treatment failure and poor survival in patients with ovarian cancer. Therefore, clarifying the molecular mechanism and identifying effective strategies to overcome drug resistance may play an important clinical impact on this malignant tumor. In our study, we found that the expression of Glycosyltransferase 8 domain containing 2 (GLT8D2) was significantly upregulated in ovarian cancer samples with CDDP (Cis-dichlorodiammine-platinum) resistance. Biological experiment demonstrate that GLT8D2 overexpression confers CDDP resistance on ovarian cancer cells; however, inhibition of GLT8D2 sensitized ovarian cancer cell lines to CDDP cytotoxicity both in vitro and in vivo. By using affinity purification/mass spectrometry (IP/MS) and reciprocal co-immunoprecipitation (co-IP) analyses, we found that GLT8D2 interacts with fibroblast growth factor receptor 1(FGFR1) in ovarian cancer cells. Furthermore, overexpression of GLT8D2 activated FGFR/PI3K signaling axis and upregulated the phosphorylation levels of FRS2a and AKT (AKT serine/threonine kinase). Importantly, pharmacological inhibition of FGFR and PI3K (phosphatidylinositol 3-kinase) signaling pathway significantly counteracted GLT8D2-induced chemoresistance and enhanced platinum’s therapeutic efficacy in ovarian cancer. Therefore, our findings suggest that GLT8D2 is a potential therapeutic target for the treatment of ovarian cancer; targeting GLT8D2/FGFR/PI3K/AKT signaling axis may represent a promising strategy to enhance platinum response in patients with chemoresistant ovarian cancer.
Highlights
Ovarian cancer, which accounts for 4% of all cancers in women, is the second common cause of gynaecologic cancer death in women worldwide [1, 2]
Aberrant expression of FGFR1 is detected in ALDHhigh (ALDH + ) pancreatic cancer cells and enhance the tumorigenesis and CSCs(cell stem cell)-like phenotype of PDAC cells with increased expression of Oct4 (POU class 5 homeobox 1), Sox-2 (SRY-box transcription factor 2), Nanog (Nanog homeobox), and c-Myc (MYC proto-oncogene, bHLH transcription factor), but targeting Fibroblast growth factor receptors (FGFRs) signalling with the selective FGFR1 inhibitor, PD173074 inhibited the proliferation and self-renewal of the panCSCs [15]
Overexpression of Glycosyltransferase 8 domain containing 2 (GLT8D2) was associated with chemoresistance in human ovarian cancer, which show that 72.7% of GLT8D2-overexpression ovarian cancer samples cases exhibited chemoresistance (Fig. 1b), suggesting that GLT8D2overexpression might be involved in ovarian cancer chemotherapy failure
Summary
Ovarian cancer, which accounts for 4% of all cancers in women, is the second common cause of gynaecologic cancer death in women worldwide [1, 2]. Compare to platinum sensitive tissues, the protein level of GLT8D2 was elevated in the ovarian cancer samples with platinum resistance by performing western blotting and IHC analyses (Fig. 1a, b, Supplementary Tables S1). Cell viability assay show that overexpression of GLT8D2 enhanced CDDP resistance compared with the vector-transfected cells, inhibition of GLT8D2 in ovarian cancer cells were more sensitive to CDDP treatment than control-transfected cells (Fig. 2b).
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