Fra-1 and c-Fos N-Terminal Deletion Mutants Impair Breast Tumor Cell Proliferation by Blocking Lipid Synthesis Activation

RACCA, ANA CRISTINA; PRUCCA, CÉSAR GERMÁN; CAPUTTO, BEATRIZ LEONOR

Frontiers in Oncology

Frontiers Media S.A

Año: 2019 vol. 9

Tumor cells require high rates of lipid synthesis to support membrane biogenesis fortheir exacerbated growth. The only two proteins known that activate phospholipidsynthesis are Fra-1 and c-Fos, two members of the AP-1 family of transcription factors.These proteins that are overexpressed in human breast malignant tumors increasethe rate of phospholipid synthesis at the endoplasmic reticulum through a mechanismindependent of their nuclear function. The aim of this study was to inhibit breast tumorcell proliferation by modulating c-Fos and Fra-1 and regulate membrane biogenesisby controlling lipid synthesis rates. The molecular mechanism by which Fra-1 andc-Fos activate phospholipid synthesis was examined. Both proteins physically associatewith the rate limiting enzyme CDP-DAG synthase through their N-terminus domainand activate it through their basic domain; neither protein associates to or activatesthe enzyme phosphatidylinositol synthase as determined through in vitro enzymaticreactions and FRET experiments. The N-terminus domain of both proteins act as negativedominant peptides that physically associate with CDP-DAG synthase but do not activateit. Proliferation of MDA-MB231 and 4T1 cells was impaired in vitro after inducing themto proliferate in the presence of the negative dominant peptides derived from Fra-1 andc-Fos. When tumors generated in Balb/c mice with the breast tumor cell line 4T1 weretreated with these negative dominant peptides, a significant reduction in tumor growthwas observed. Consequently, these Fra-1 and c-Fos negative dominant peptides can beexploited as a new therapeutic strategy to impair breast tumor cell proliferation.