Abstract
High grade serous ovarian cancer (HGSOC) is the most common and aggressive type of ovarian cancer. Platinum resistance is a common occurrence in HGSOC and a main cause of tumor relapse resulting in high patient mortality rates. Recurrent ovarian cancer is enriched in aldehyde dehydrogenase (ALDH)+ ovarian cancer stem cells (OCSCs), which are resistant to platinum agents. We demonstrated that acute platinum treatment induced a DNA damage-dependent decrease in BRCA1 levels through BRCA1 promoter DNA hypermethylation. In a parallel pathway associated with G2/M arrest, platinum treatment also induced an increase in expression of NAMPT, the rate limiting regulator of NAD+ production from the salvage pathway, and NAD+ levels, the cofactor required for ALDH activity. Both decreased BRCA1 and increased NAD+ levels were required for the platinum-induced enrichment of OCSCs, and inhibition of both DNA methyltransferases (DNMT) and NAMPT synergistically abrogated the platinum-induced increase in OCSCs. We conclude that these two separate pathways lead to platinum-induced OCSC enrichment, providing preclinical evidence that in the neoadjuvant setting, combining DNMT and NAMPT inhibitors with platinum has the potential to reduce OC reoccurrence.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Conflict of interest: The authors declare no conflict of interest.