Endothelial Cells Promote Docetaxel Resistance of Prostate Cancer via FGF2/ERG/Akt/mTOR Signaling Pathway

Abstract Background Docetaxel is a first-line chemotherapy for the treatment of patients with castration-resistant prostate cancer (CRPC). Despite the good initial response of docetaxel, drug resistance will inevitably occur. Mechanisms underlying docetaxel resistance are not well elaborated. Endothelial cells (ECs) have been implicated in the progression and metastasis of prostate cancer (PCa). However, little attention has been paid to the role of ECs in the development of docetaxel resistance in PCa. Methods Here, we sought to investigate the function and mechanism of ECs involving in the docetaxel resistance of PCa. The 22Rv1 and C4-2B PCa cell lines were cultured with or without human umbilical vein endothelial cells (HUVEC). The proliferation of each PCa cell line was assessed by CCK8 and EdU assays. Cell viability of each PCa cell line treated with docetaxel was evaluated by CCK8. Apoptosis was measured by flow cytometry. Quantitative reverse transcription (RT)-PCR assay was used to determine the expression of ETS related gene (ERG) in each PCa cell line and FGF2 in HUVEC. The proteins including ERG, Caspase3, PARP, Akt, p-Akt, mTOR and p-mTOR were quantified by western blotting. ERG overexpressing C4-2B cells(C4-2B-ERG) were constructed by transfection with pLenti6.3-ERG lentivirus. C4-2B-ERG cells were knocked down by transfecting with ERG siRNAs. Differentially expressed cytokines between the serum-free media from 22Rv1 and 22Rv1/HUVEC co-culture system were detected by human cytokine array and determined by ELISA assay. Tumors were induced in mice by injecting 22Rv1 cells with or without HUVEC and treated with docetaxel. Tumor growth and apoptosis were examined by immunohistochemistry and TUNEL respectively. Results ECs promoted proliferation and inhibited apoptosis in PCa cells (in vitro) and mouse xenograft tumors induced by these cells (in vivo) under docetaxel treatment. ECs secreted FGF2 to induce ERG expression and activate the Akt/mTOR signaling pathway in PCa cells contributing to docetaxel resistance. Blocking FGF2 could reverse the enhancing effects of HUVEC on docetaxel resistance in PCa cells. Inhibition of the Akt/mTOR signaling pathway could alleviate chemoresistance mediated by ERG. Conclusion ECs promote docetaxel resistance via FGF2/ERG/Akt/mTOR signaling pathway in PCa cells. Targeting FGF/ FGFR signaling may represent a promising therapeutic strategy to overcome docetaxel resistance.