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

被引:16
作者
Zhao, Cheng [1 ,2 ,3 ]
Yang, Zi-yi [1 ,2 ,3 ]
Zhang, Jian [1 ,2 ,3 ]
Li, Ou [1 ,2 ,3 ]
Liu, Shi-lei [1 ,2 ,3 ]
Cai, Chen [1 ,2 ,3 ]
Shu, Yi-jun [1 ,2 ,3 ]
Pan, Li-jia [1 ,2 ,3 ]
Gong, Wei [1 ,2 ,3 ]
Dong, Ping [1 ,2 ,3 ]
机构
[1] Shanghai Jiao Tong Univ, Lab Gen Surg, Sch Med, Xinhua Hosp, 1665 Kongjiang Rd, Shanghai 200092, Peoples R China
[2] Shanghai Jiao Tong Univ, Dept Gen Surg, Sch Med, Xinhua Hosp, 1665 Kongjiang Rd, Shanghai 200092, Peoples R China
[3] Shanghai Key Lab Biliary Tract Dis Res, 1665 Kongjiang Rd, Shanghai 200092, Peoples R China
基金
中国国家自然科学基金;
关键词
Chromosome region maintenance 1; Gallbladder cancer; KPT-330; Apoptosis; Autophagy; NUCLEOCYTOPLASMIC TRANSPORT; NUCLEAR EXPORT; CELLS; COMBINATION; INDUCTION; SURVIVAL; TARGET; AMPK;
D O I
10.1186/s12967-022-03635-w
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Background Gallbladder cancer (GBC) is a highly aggressive malignant cancer in the biliary system with poor prognosis. XPO1 (chromosome region maintenance 1 or CRM1) mediates the nuclear export of several proteins, mainly tumor suppressors. Thus, XPO1 functions as a pro-oncogenic factor. KPT-330 (Selinexor) is a United States Food and Drug Administration approved selective inhibitor of XPO1 that demonstrates good therapeutic effects in hematologic cancers. However, the function of XPO1 and the effect of KPT-330 have not been reported in GBC. Methods We analyzed the correlation between XPO1 expression levels by q-PCR and clinical features of GBC patients. Cell proliferation assays were used to analyze the in vitro antitumor effects of XPO1 inhibitor KPT-330. mRNA sequencing was used to explore the underlying mechanisms. Western blot was performed to explore the relationship between apoptosis and autophagy. The in vivo antitumor effect of KPT-330 was investigated in a nude mouse model of gallbladder cancer. Results We found that high expression of XPO1 was related to poor prognosis of GBC patients. We observed that XPO1 inhibitor KPT-330 inhibited the proliferation of GBC cells in vitro. Furthermore, XPO1 inhibitor KPT-330 induced apoptosis by reducing the mitochondrial membrane potential and triggering autophagy in NOZ and GBC-SD cells. Indeed, XPO1 inhibitor KPT-330 led to nuclear accumulation of p53 and activated the p53/mTOR pathway to regulate autophagy-dependent apoptosis. Importantly, KPT-330 suppressed tumor growth with no obvious toxic effects in vivo. Conclusion XPO1 may be a promising prognostic indicator for GBC, and KPT-330 appears to be a potential drug for treating GBC effectively and safely.
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页数:17
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