烟酰胺磷酸核糖转移酶
顺铂
衰老
癌症研究
癌症干细胞
卵巢癌
癌症
医学
NAD+激酶
生物
内科学
干细胞
化疗
细胞生物学
生物化学
酶
作者
Timothy Nacarelli,Takeshi Fukumoto,Joseph A. Zundell,Nail Fatkhutdinov,Stéphanie Jean,Mark G. Cadungog,Mark E. Borowsky,Rugang Zhang
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2020-02-14
卷期号:80 (4): 890-900
被引量:82
标识
DOI:10.1158/0008-5472.can-19-2830
摘要
Epithelial ovarian cancer (EOC) is the most lethal of gynecologic malignancies. The standard-of-care treatment for EOC is platinum-based chemotherapy such as cisplatin. Platinum-based chemotherapy induces cellular senescence. Notably, therapy-induced senescence contributes to chemoresistance by inducing cancer stem-like cells (CSC). However, therapeutic approaches targeting senescence-associated CSCs remain to be explored. Here, we show that nicotinamide phosphoribosyltransferase (NAMPT) inhibition suppresses senescence-associated CSCs induced by platinum-based chemotherapy in EOC. Clinically applicable NAMPT inhibitors suppressed the outgrowth of cisplatin-treated EOC cells both in vitro and in vivo. Moreover, a combination of the NAMPT inhibitor FK866 and cisplatin improved the survival of EOC-bearing mice. These phenotypes correlated with inhibition of the CSCs signature, which consists of elevated expression of ALDH1A1 and stem-related genes, high aldehyde dehydrogenase activity, and CD133 positivity. Mechanistically, NAMPT regulates EOC CSCs in a paracrine manner through the senescence-associated secretory phenotype. Our results suggest that targeting NAMPT using clinically applicable NAMPT inhibitors, such as FK866, in conjunction with platinum-based chemotherapy represents a promising therapeutic strategy by suppressing therapy-induced senescence-associated CSCs. SIGNIFICANCE: This study highlights the importance of NAMPT-mediated NAD+ biosynthesis in the production of cisplatin-induced senescence-associated cancer stem cells, as well as tumor relapse after cisplatin treatment.
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