Oncotarget

Research Papers:

Expression and function of nuclear receptor coactivator 4 isoforms in transformed endometriotic and malignant ovarian cells

Stephanie Rockfield, Idhaliz Flores and Meera Nanjundan _

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Oncotarget. 2018; 9:5344-5367. https://doi.org/10.18632/oncotarget.23747

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Abstract

Stephanie Rockfield1, Idhaliz Flores2 and Meera Nanjundan1

1Department of Cell Biology, Microbiology, and Molecular Biology, University of South Florida, Tampa, FL, USA

2Department of Basic Sciences-Microbiology, Ponce Health Sciences University and School of Medicine, Ponce Research Institute, Ponce, Puerto Rico

Correspondence to:

Meera Nanjundan, email: mnanjund@usf.edu

Keywords: NCOA4; ferritinophagy; epithelial ovarian cancer; iron; cell survival

Received: July 14, 2017     Accepted: December 22, 2017     Published: December 28, 2017

ABSTRACT

Iron is proposed to contribute to the transition from endometriosis to specific subtypes of ovarian cancers (OVCAs). Regulation of intracellular iron occurs via a ferritinophagic process involving NCOA4 (Nuclear Receptor Coactivator 4), represented by two major isoforms (NCOA4α and NCOA4β), whose contribution to ovarian cancer biology remains uninvestigated. We thus generated transformed endometriotic cells (via HRASV12A, c-MYCT58A, and p53 inactivation) whose migratory potential was increased in response to conditioned media from senescent endometriotic cells. We identified elevated NCOA4 mRNA in transformed endometriotic cells (relative to non-transformed). Knockdown of NCOA4 increased ferritin heavy chain (FTH1) and p21 protein which was accompanied by reduced cell survival while NCOA4β overexpression reduced colony formation. NCOA4α and NCOA4β mRNA were elevated in malignant versus non-malignant gynecological cells; NCOA4α protein was increased in the assessed malignant cell lines as well as in a series of OVCA subtypes (relative to normal adjacent tissues). Further, NCOA4 protein expression was regulated in a proteasome- and autophagy-independent manner. Collectively, our results implicate NCOA4 in ovarian cancer biology in which it could be involved in the transition from precursors to OVCA.


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