Autophagy and cancer stem cells or tumor-initiating cells in human breast cancer
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1
INSERM U1151-CNRS UMR 8253, Institut Necker Enfants-Malades (INEM), France
Background and aim. Breast cancer tissue contains a small population of cells that have the ability to self-renew; these cells are known as cancer stem-like cells (CSCs; Aldehyde dehydrogenase 1 positive cells, ALDH+. We have recently shown that autophagy is essential for the tumorigenicity of these CSCs. Salinomycin (Sal), a K+/H+ ionophore, has recently been shown to be at least 100 times more effective than paclitaxel to reduce the proportion of breast CSCs. However, its mechanisms of action are still unclear.
Methods. To elucidate the effect of Sal on autophagic capacity of breast cancer cell lines and CSCs/progenitor cells, we used various breast cancer cell lines, including HMLER, HMLER CD24low/- (rich in the ‘stemness’ phenotype), and MCF-7 cells from non-adherent mammosphere cultures providing an adequate model in which the proportion of mammary CSCs/progenitor cells is increased. To get further insights into the potential involvement of autophagic flux inhibition in the susceptibility of CSCs to Sal-induced apoptosis, HLMER cells were sorted into two subpopulations on the basis of their ALDH1 activity using an Aldefluor assay and using flow cytometry cell sorting.
Results. In the work, we demonstrate that Sal blocked both autophagy flux and lysosomal proteolytic activity in both CSCs and non-CSCs derived from breast cancer cells. GFP-LC3 staining combined with fluorescent dextran uptake and LysoTracker-Red staining showed that autophagosome / lysosome fusion was not altered by Sal treatment. However, the lysosomal protein degradation was inhibited by Sal treatment, as demonstrated by the analysis of the rate of long-lived protein degradation, DQ-BSA assay and measurement of cathepsin activity. More importantly, our data indicated that Sal has a relatively greater suppressant effect on autophagic flux in the ALDH(+) population than in the ALDH(-) population. Moreover, this differential effect on autophagic flux between the ALDH(-) population versus the ALDH(+) population correlated with an increase in apoptosis in the ALDH(+) population. ATG7 depletion did not change the proapoptotic capacity of Sal in the ALDH(+) population.
Conclusions / Discussion. Our findings provide new insights into how the autophagy-lysosomal pathway contributes to the ability of Sal to target CSCs in vitro. Next our research will focus on the role of acid compartments (such as lysosomes) in the regulation of autophagy and ‘stem-like’ signaling in breast CSCs contributing in their maintenance, their survival and their resistance to cell death induced by cancer therapy.
Acknowledgements
This work was supported by institutional funding from INSERM, University Paris-Sud 11, and grants from the PHC-PFCC (programme français de cooperation avec la Chine), the ANR (Agence Nationale de la Recherche), the INCa (Institut National du Cancer) and the ‘Ligue Nationale contre le Cancer’.
Keywords:
breast cancer,
cancer stem cells (CSC),
Autophagy,
salinomycin,
Cell Death
Conference:
4th Annual Meeting of the International Society of Proton Dynamics in Cancer, Garching, Germany, 10 Oct - 12 Oct, 2013.
Presentation Type:
Abstract
Topic:
6. pH control of immune functions and tumor cell plasticity
Citation:
Hamaï
A,
Yue
W,
Botti
J,
Bauvy
C,
Codogno
P and
Mehrpour
M
(2014). Autophagy and cancer stem cells or tumor-initiating cells in human breast cancer.
Front. Pharmacol.
Conference Abstract:
4th Annual Meeting of the International Society of Proton Dynamics in Cancer.
doi: 10.3389/conf.fphar.2014.61.00020
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Received:
21 Jan 2014;
Published Online:
07 Feb 2014.
*
Correspondence:
Mr. Patrice Codogno, INSERM U1151-CNRS UMR 8253, Institut Necker Enfants-Malades (INEM), Paris, 75993 Paris cedex 14, France, patrice.codogno@inserm.fr
Ms. Maryam Mehrpour, INSERM U1151-CNRS UMR 8253, Institut Necker Enfants-Malades (INEM), Paris, 75993 Paris cedex 14, France, maryam.mehrpour@inserm.fr