NAMPT Inhibition Suppresses Cancer Stem-like Cells Associated with Therapy-Induced Senescence in Ovarian Cancer

Abstract

Epithelial ovarian cancer (EOC) is the most lethal of gynecologic malignancies. The standard-of-care treatment for EOC is platinumbased 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 senescenceassociated 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 EOCbearing 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 senescenceassociated CSCs.Significance: This study highlights the importance of NAMPTmediated NAD þ biosynthesis in the production of cisplatininduced senescence-associated cancer stem cells, as well as tumor relapse after cisplatin treatment.

Long non-coding RNA HAL suppresses the migration and invasion of serous ovarian cancer by inhibiting EMT signaling pathway

“…Because of the location of SOC in pelvic cavity, the symptoms of SOC are hidden, many women have entered a progressive stage when the SOC was discovered [3]. The standard initial treatment for SOC is tumor cell reduction followed by platinum or paclitaxel chemotherapy [4]. Despite such aggressive treatment, recurrence and metastasis rates remain high [5].…”

Transcriptome-based Stemness Indices Analysis Reveals Platinum-based Chemotheraputic Response Indicators in Advanced-stage Serous Ovarian Cancer

“…This con rmed the uncontrolled cell proliferation was a core characteristic of OC cells as well as the ovarian cancer stem cells (OVSCSs). In the results of the KEGG pathway, we found that the pathway "Cell cycle" [18,19], "Cellular senescence" [13][14][15], "p53 signaling pathway" [16,17], and "Platinum drug resistance" were closely associated with platinum sensitivity according to previous reports. A recent review had summarized that an insu cient dose of platinum might lead to a cytostatic response, named dormancy, rather than cytotoxic response, through inducing cell cycle arrest and cellular senescence [26].…”

“…These key genes were mainly involved in the pathways of the cell cycle ( Figure 3B). Interestingly, the selected key genes were also enriched to the platinum response-associated pathways "cellular senescence" [13][14][15], "p53 signaling pathway" [16,17], and "Platinum drug resistance" ( Figure 3B). Cell cycle arrest was also the main molecular mechanism of the platinum anticancer effect [18,19].…”

Long non-coding RNA THOR promotes Ovarian Cancer cells progression via IL-6/STAT3 pathway

“…It was reported that CD133 was well-accepted ovarian cancer stem cells (CSCs) marker (15). As shown in Figure 4A, THOR expression was dramatically increased in CD133-positive ovarian CSCs.…”