FGFR3S249C mutation promotes chemoresistance by activating Akt signaling in bladder cancer cells

Xina Xie; Jiatian Lin; Yuantang Zhong; Mianheng Fu; Aifa Tang

doi:10.3892/etm.2019.7672

FGFR^3S249C mutation promotes chemoresistance by activating Akt signaling in bladder cancer cells

Exp Ther Med. 2019 Aug;18(2):1226-1234. doi: 10.3892/etm.2019.7672. Epub 2019 Jun 13.

Authors

Xina Xie^{1

2}, Jiatian Lin³, Yuantang Zhong⁴, Mianheng Fu², Aifa Tang^{1

2}

Affiliations

¹ Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China.
² Institute of Translational Medicine, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Health Science Center, Shenzhen, Guangdong 518035, P.R. China.
³ Department of Minimally Invasive Intervention, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China.
⁴ Department of Urinary Surgery, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Health Science Center, Shenzhen, Guangdong 518035, P.R. China.

Abstract

Fibroblast growth factor receptor 3 (FGFR3) is a high frequency mutant gene in bladder cancer (BCa) and has become a promising therapeutic target due to its involvement in cell proliferation and migration. However, whether and how FGFR3 mutations affects BCa cell chemosensitivity is unknown. The current study aimed to elucidate the role of the FGFR3^S249C mutation in the development of chemoresistance in BCa cells. The results revealed that 97-7 (FGFR3^S249C) cells had decreased sensitivity to cisplatin compared with 5637 (FGFR3^WT) and T24 (FGFR3^WT) cells. The ratio of phosphorylated-Akt/total-Akt was higher in 97-7 (FGFR3^S249C) cells, which was reversed by knockdown of FGFR3. Furthermore, inhibition of Akt signaling by GDC0068 or LY294002 increased the cisplatin sensitivity of 97-7 (FGFR3^S249C) cells. GDC0068 or LY294002 was also revealed to augment the effects of cisplatin on 97-7 (FGFR3^S249C) cell proliferation and apoptosis. The results of the present study demonstrated that the FGFR3^S249C mutation promotes chemoresistance in BCa cells by activating the Akt signaling pathway. The FGFR3^S249C mutation may therefore be used as a predictor of chemosensitivity in patients with BCa.

Keywords: Akt signaling; bladder cancer; chemoresistance; cisplatin; fibroblast growth factor receptor 3S249C mutation.