Inhibition of XPO1 with KPT-330 induces autophagy-dependent apoptosis in gallbladder cancer by activating the p53/mTOR pathway

• DOI: 10.1186/s12967-022-03635-w
• Publication Date: 2022-09-30T10:03:27Z
• Authors: Cheng Zhao; Zi-yi Yang; Jian Zhang; Ou Li; Shi-lei Liu; Chen Cai; Yi-jun Shu; Li-jia Pan; Wei Gong; Ping Dong
• Keywords: Gallbladder Cancer; RPTOR

Gallbladder cancer (GBC) is a highly aggressive malignant in the biliary system with poor prognosis. XPO1 (chromosome region maintenance 1 or CRM1) mediates nuclear export of several proteins, mainly tumor suppressors. Thus, functions as pro-oncogenic factor. KPT-330 (Selinexor) United States Food and Drug Administration approved selective inhibitor that demonstrates good therapeutic effects hematologic cancers. However, function effect have not been reported GBC.We analyzed correlation between expression levels by q-PCR clinical features GBC patients. Cell proliferation assays were used to analyze vitro antitumor KPT-330. mRNA sequencing was explore underlying mechanisms. Western blot performed relationship apoptosis autophagy. The vivo investigated nude mouse model gallbladder cancer.We found high related prognosis We observed inhibited cells vitro. Furthermore, induced reducing mitochondrial membrane potential triggering autophagy NOZ GBC-SD cells. Indeed, led accumulation p53 activated p53/mTOR pathway regulate autophagy-dependent apoptosis. Importantly, suppressed growth no obvious toxic vivo.XPO1 may be promising prognostic indicator for GBC, appears drug treating effectively safely.