Targeting sphingosine kinase 2 suppresses cell growth and synergizes with BCL2/BCL-XL inhibitors through NOXA-mediated MCL1 degradation in cholangiocarcinoma

被引:0
|
作者
Ding, Xiwei [1 ]
Zhang, Yiyang [2 ]
Huang, Tianlu [1 ]
Xu, Guifang [1 ]
Peng, Chunyan [1 ]
Chen, Gang [3 ]
Kong, Bo [1 ,4 ]
Friess, Helmut [4 ]
Shen, Shanshan [1 ]
Lv, Ying [1 ]
Roberts, Lewis R. [5 ,6 ]
Wang, Lei [1 ]
Zou, Xiaoping [2 ]
机构
[1] Nanjing Univ, Dept Gastroenterol, Affiliated Hosp, Med Sch,Nanjing Drum Tower Hosp, Nanjing 210008, Jiangsu, Peoples R China
[2] Nanjing Med Univ, Nanjing Drum Tower Hosp, Clin Coll, Dept Gastroenterol, Nanjing 210008, Jiangsu, Peoples R China
[3] Wenzhou Med Univ, Div Hepatobiliary Surg, Affiliated Hosp 1, Wenzhou 325000, Zhejiang, Peoples R China
[4] Tech Univ Munich, Dept Surg, D-80333 Munich, Germany
[5] Mayo Clin, Coll Med, Div Gastroenterol & Hepatol, Rochester, MN 55905 USA
[6] Mayo Clin, Ctr Canc, Rochester, MN 55905 USA
来源
AMERICAN JOURNAL OF CANCER RESEARCH | 2019年 / 9卷 / 03期
基金
中国国家自然科学基金;
关键词
Cholangiocarcinoma; ABC294640; NOXA; MCL1; ABT-263; obatoclax; ACUTE LYMPHOBLASTIC-LEUKEMIA; ACUTE MYELOGENOUS LEUKEMIA; THERAPEUTIC TARGETS; ABC294640; APOPTOSIS; 1-PHOSPHATE; COMBINATION; EXPRESSION; EFFICACY; ABT-263;
D O I
暂无
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Sphingosine kinase 2 (SPHK2) is a key factor within sphingolipid metabolism, responsible for the conversion of pro-apoptotic sphingosine to the pro-survival sphingosine-1-phosphate. We have previously shown that ABC294640, a first-in-class SPHK2 inhibitor, inhibits growth of cholangiocarcinoma cells. In a Phase I study of ABC294640 in tumors, the best response was achieved in a cholangiocarcinoma patient. These data suggest SPHK2 as a novel therapeutic target of cholangiocarcinoma. However, the antitumor mechanism of ABC294640 in cholangiocarcinoma remains not clear. In the current study, we found that ABC294640 upregulated expression of pro-apoptotic NOXA. In cholangiocarcinoma patients, high NOXA mRNA expression was associated with better overall survival. Also, SPHK2 mRNA expression was negatively correlated with NOXA mRNA expression. NOXA is known to degrade MCL1, an anti-apoptotic BCL2 protein. We showed that ABC294640 directed MCL1 for proteasome degradation. Knockdown of NOXA prevented ABC294640-induced MCL1 degradation and apoptosis. In addition, ABC294640 had a synergistic effect with BCL2/BCL-XL inhibitors ABT-263 and Obatoclax in inhibiting cell growth. Combined treatment with ABC294640 and BCL2/BCL-XL inhibitors induced potent apoptosis. Silencing of MCL1 also potentiated ABT-263-induced cytotoxicity. Furthermore, we found that both SPHK2 and MCL1 protein expression were significantly higher in cholangiocarcinoma than that in nontumoral bile ducts. SPHK2 expression correlated significantly with MCL1 expression. Our study reveals that ABC294640 inhibits cholangiocarcinoma cell growth and sensitizes the antitumor effect of BCL2/BCL-XL inhibitors through NOXA-mediated MCL1 degradation. Combinations of ABC294640 with BCL2/BCL-XL inhibitors may provide novel strategies for the treatment of cholangiocarcinoma.
引用
收藏
页码:546 / 561
页数:16
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