American Association for Cancer Research
00085472can192830-sup-228736_3_supp_5951226_q2vxgz.pdf (1.29 MB)

Supplementary Figure 5 from NAMPT Inhibition Suppresses Cancer Stem-like Cells Associated with Therapy-Induced Senescence in Ovarian Cancer

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journal contribution
posted on 2023-03-31, 03:28 authored by Timothy Nacarelli, Takeshi Fukumoto, Joseph A. Zundell, Nail Fatkhutdinov, Stephanie Jean, Mark G. Cadungog, Mark E. Borowsky, Rugang Zhang

Figure S5 shows that NMN supplementation during cisplatin-induced senescence of ovarian cancer cells promotes cancer stem-like cells.



US Department of Defense

Honorable Tina Brozman Foundation

Ovarian Cancer Research Alliance

Cancer Centre Support



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. 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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