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Hydroxytyrosol inhibits chemokine C-C motif ligand 5 mediated aged quiescent fibroblast-induced stimulation of breast cancer cell proliferation

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Abstract

Cancer is an age-associated disease. Although the mechanisms of age-associated increase in cancer incidence are not completely understood, it is believed that the tumor stromal environment significantly influences epithelial malignancy. Fibroblasts are a major cell type in the stroma and, under normal conditions, fibroblasts reside in the quiescent state. Cellular quiescence is a reversible process where cells enter into the proliferative cycle and then exit back to quiescence. We have shown previously that quiescent fibroblasts lose their proliferative capacity as they age, and we defined this mode of cellular aging as chronological life span. Using conditioned media and co-culture experiments, results from this study show that normal human fibroblasts (NHFs) nearing the end of their chronological life span stimulate the proliferation of MB231 and MCF7 human breast epithelial cancer cells. Chemokine C-C motif ligand 5 (CCL5) expression was found to be approximately 8-fold higher in old compared to that in young quiescent NHFs, which correlated with an increase in the ERK1/2-cyclin D1 pro-proliferative pathway in MB231 cells. Conditioned media treated with anti-CCL5 antibody suppressed the activation of the ERK1/2-cyclin D1 pathway and proliferation of MB231 cells. Hydroxytyrosol, a dietary polyphenol and an active ingredient of olive, inhibited CCL5 expression in aging quiescent NHFs. This inhibition was associated with NHFs inability to activate the ERK1/2-cyclin D1 pathway and enhance proliferation of MB231 cells. These results show that fibroblasts nearing the end of their chronological life span promote proliferation of human breast epithelial cancer cells and dietary polyphenols inhibit this process.

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Abbreviations

CCL5:

Chemokine C-C motif ligand 5

CCR:

Chemokine C-C motif ligand receptor

ERK1/2:

Extracellular-signal-regulated kinases 1 and 2

MnSOD:

Manganese superoxide dismutase

NHFs:

Normal human fibroblasts

ROS:

Reactive oxygen species

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Acknowledgments

We thank Mr. Justin Fishbaugh at the Flow Cytometry Core facility for assisting with the flow cytometry methods, and Mr. Tom Moninger of the Central Microscopy Research facility for assistance with the microscopy methods. Funding from NIH 2R01 CA111365 (PCG, EHS, and ALK), NIH T32CA078586 (JL), and Iowa Center for Research by Undergraduates Scholarship (MG) supported this work.

Financial support

Funding from NIH 2R01 CA111365 supported PCG, EHS, and ALK; NIH T32CA078586 supported JL; and Iowa Center for Research by Undergraduates Scholarship supported MG.

Conflicts of interest

None.

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Authors and Affiliations

  1. Free Radical and Radiation Biology Division, Department of Radiation Oncology, University of Iowa, Iowa City, IA, 52242-1181, USA

    Ehab H. Sarsour, Amanda L. Kalen, John T. Lafin & Prabhat C. Goswami

  2. Integrated DNA Technologies, Inc., 1710 Commercial Park, Coralville, IA, 52241, USA

    Monali Goswami

Authors
  1. Ehab H. Sarsour
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  2. Monali Goswami
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  3. Amanda L. Kalen
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  4. John T. Lafin
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  5. Prabhat C. Goswami
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Correspondence to Prabhat C. Goswami.

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Sarsour, E.H., Goswami, M., Kalen, A.L. et al. Hydroxytyrosol inhibits chemokine C-C motif ligand 5 mediated aged quiescent fibroblast-induced stimulation of breast cancer cell proliferation. AGE 36, 1213–1224 (2014). https://doi.org/10.1007/s11357-014-9645-0

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  • DOI: https://doi.org/10.1007/s11357-014-9645-0

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