C-Src functionality controls self-renewal and glucose metabolism in MCF7 breast cancer stem cells.

Víctor Mayoral-Varo,María Pilar Sánchez-Bailón,Miguel Ángel Fernández-Moreno,Óscar H Martínez-Costa,Sergio Ciordia,Cristina González-Páramos,Annarica Calcabrini,Juan J Aragón,Jorge Martín-Pérez,David Hardisson,Antimo Migliaccio

doi:10.1371/journal.pone.0235850

Abstract

Deregulation of Src kinases is associated with cancer. We previously showed that SrcDN conditional expression in MCF7 cells reduces tumorigenesis and causes tumor regression in mice. However, it remained unclear whether SrcDN affected breast cancer stem cell functionality or it reduced tumor mass. Here, we address this question by isolating an enriched population of Breast Cancer Stem Cells (BCSCs) from MCF7 cells with inducible expression of SrcDN. Induction of SrcDN inhibited self-renewal, and stem-cell marker expression (Nanog, Oct3-4, ALDH1, CD44). Quantitative proteomic analyses of mammospheres from MCF7-Tet-On-SrcDN cells (data are available via ProteomeXchange with identifier PXD017789, project DOI: 10.6019/PXD017789) and subsequent GSEA showed that SrcDN expression inhibited glycolysis. Indeed, induction of SrcDN inhibited expression and activity of hexokinase, pyruvate kinase and lactate dehydrogenase, resulting in diminished glucose consumption and lactate production, which restricted Warburg effect. Thus, c-Src functionality is important for breast cancer stem cell maintenance and renewal, and stem cell transcription factor expression, effects linked to glucose metabolism reduction.

Highlights

Mammary gland stem cells are capable of self-renewal and to generate all differentiated progeny of the gland [1, 2]
To determine the role of SrcDN in the self-renewal of the enriched subpopulation of breast cancer stem cells (BCSCs), we isolated CD24- (ESA+-CD44+-CD24-) and CD24+ (ESA+-CD44+-CD24+) cell populations derived from MCF7-Tet-On-SrcDN by fluorescence-activated cell sorting (FACS)
Cells were first sorted as ESA+ and for being CD44+-CD24- (1.6%), while the CD44+-CD24+ represented 98.4% of total cell population (Fig 1A, isotype controls shown in S1 Fig in S1 File)

Summary

Introduction

Mammary gland stem cells are capable of self-renewal and to generate all differentiated progeny of the gland [1, 2]. Because of their long lifespan, they can accumulate mutations to become breast cancer stem cells (BCSCs). C-Src controls breast cancer stem cells accession number: PXD017789, project DOI: 10.

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Results

Conclusion