GW4064 inhibits migration and invasion through cathepsin B and MMP2 downregulation in human bladder cancer

Urothelial carcinoma is an important health issue worldwide. Previous studies have clearly shown that cigarette smoking is the leading risk factor for bladder cancer (BC) [1]. Social characteristics, including sex, race, age, obesity and alcohol consumption, are also risk factors for BC [2,3]. Moreover, individuals with occupational exposure, such as those who work closely with tobacco, dye and rubber, are also a high-risk group, and occupational exposure accounts for 5–6 % of the attributable risk for BC [[3], [4], [5]].

In clinical therapeutics, transurethral resection of bladder tumor is usually considered for non-muscle-invasive bladder cancer (NMIBC). A resectoscope is utilized in the surgery to remove the tumors in pieces. However, this surgery is challenging because it may present opportunities for tumor cell implantation into healthy bladder tissues [6]. In addition, NMIBC recurrence and progression have been reported by many researchers. The five-year recurrence rate and progression rate are approximately 78 % and 45 %, respectively [7]. Approximately 20 % of bladder cancer cases are muscle-invasive bladder cancer (MIBC). Regardless of the therapeutic approach, including radical cystectomy and pelvic lymph node dissection, disseminated micrometastasis at distant sites still occurs in approximately 50 % of patients [8,9].

GW4064 is a potent and selective nonsteroidal ligand for the nuclear bile acid receptor farnesoid X receptor (FXR; NR1H4) [10]. Currently, GW4064 has been utilized in research in cervical cancer, colorectal cancer, and breast cancer. In cervical cancer, GW6064 reduces the viability of CaSki, HeLa, and SiHa cervical cancer cells through the induction of G1 arrest and apoptosis [11]. In colorectal cancer, GW4064 suppresses proliferation and autophagy and triggers apoptosis in HCT116, SW480, and DLD1 colorectal cancer cells [12]. In breast cancer, GW4064 inhibits cancer-associated fibroblast (CAF) migration, stress fiber formation, and contractility by reducing the secretion of soluble factors, such as insulin-like growth factor-1 and TGF-β [13]. However, the effect of GW4064 on migration and invasion in bladder cancer has not yet been investigated.

Our preceding studies showed that FXR overexpression may lead to inhibition of bladder cancer cell migration, invasion, and angiogenesis through downregulation of cholesterol biosynthesis and the proteosome degradation pathway [14]. In this investigation, we aimed to explore whether the FXR agonist GW4064 contributes to anticancer effects in human urothelial carcinoma. Hence, the effects of GW4064 on cell migration and invasion were explored in both muscle and non-muscle-invasive bladder cancer cells.

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