NFkB promotes ovarian tumorigenesis via classical pathways that support proliferative cancer cells and alternative pathways that support ALDHþ cancer stem–like cells

Carrie D. House, Elizabeth Jordan, Lidia Hernandez, Michelle Ozaki, Jana M. James, Marianne Kim, Michael J. Kruhlak, Eric Batchelor, Fathi Elloumi, Margaret C. Cam, Christina M. Annunziata

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

Understanding the mechanisms supporting tumor-initiating cells (TIC) is vital to combat advanced-stage recurrent cancers. Here, we show that in advanced ovarian cancers NFkB signaling via the RelB transcription factor supports TIC populations by directly regulating the cancer stem-like associated enzyme aldehyde dehydrogenase (ALDH). Loss of RelB significantly inhibited spheroid formation, ALDH expression and activity, chemoresistance, and tumorigenesis in subcutaneous and intrabursal mouse xenograft models of human ovarian cancer. RelB also affected expression of the ALDH gene ALDH1A2. Interestingly, classical NFkB signaling through the RelA transcription factor was equally important for tumorigenesis in the intrabursal model, but had no effect on ALDH. In this case, classical signaling via RelA was essential for proliferating cells, whereas the alternative signaling pathway was not. Our results show how NFkB sustains diverse cancer phenotypes via distinct classical and alternative signaling pathways, with implications for improved understanding of disease recurrence and therapeutic response.

Original languageEnglish (US)
Pages (from-to)6927-6940
Number of pages14
JournalCancer Research
Volume77
Issue number24
DOIs
StatePublished - Dec 15 2017

Bibliographical note

Funding Information:
This study was supported by the NCI intramural research program ZIA BC 011054 (to C.M. Annunziata) and 1K99CA204727 (to C.D. House).

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