Overexpression of glycosyltransferase 8 domain containing 2 confers ovarian cancer to CDDP resistance by activating FGFR/PI3K signalling axis

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.

FGF/FGFR-Dependent Molecular Mechanisms Underlying Anti-Cancer Drug Resistance

“…Expression of FGF2 by endothelial cells promoted prostate cancer cells proliferation and led to the acquisition of docetaxel resistance via activation of the AKT/mTOR pathway and upregulation of the erythroblast transformation specific related gene [ 91 ]. In ovarian cancer, the FGFR/PI3K/AKT pathway has been implicated in the development of cisplatin resistance induced by the GLT8D (glycosylotransferase 8 domain containing2) protein through the interaction with FGFR1 and the subsequent signaling activation [ 92 ].…”

Bioinformatic analysis and machine learning to identify the diagnostic biomarkers and immune infiltration in adenomyosis

“…GLT8D2 is a member of the glycosyltransferase eight family that contributes to the pathogenesis of non-alcoholic fatty liver disease by regulating the accumulation of triglycerides ( Wei et al, 2013 ). GLT8D2 could contribute to FGFR/PI3K/AKT activation and induce chemoresistance in ovarian cancer ( Huang et al, 2021 ). It may also be involved in the immune system and pathogenesis of human pulmonary artery hypertension ( Bai et al, 2021 ).…”

Preclinical Evaluation of Novel Tyrosine-Kinase Inhibitors in Medullary Thyroid Cancer

“…These pathways are known to be relevant mitogenic signaling pathways activated during the onset of drug resistance in tumors [ 6 , 50 , 51 , 52 ]. The potential role of FGF and VEGF signaling pathways in carcinogenesis and tumor progression has been assessed in several neoplasms [ 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 ]. Although less studied in MTC, these pathways appear to be involved in thyroid cancer progression.…”