CCL5 promotes proliferation of MCF-7 cells through mTOR-dependent mRNA translation

The proliferative capacity of cancer cells is regulated by factors intrinsic to cancer cells and by secreted factors in the microenvironment. Here, we investigated the proto-oncogenic potential of the chemokine receptor, CCR5, in MCF-7 breast cancer cell lines. At physiological levels, CCL5, a ligan...

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Bibliographic Details
Published in:Biochemical and biophysical research communications 2009-09, Vol.387 (2), p.381-386
Main Authors: Murooka, Thomas T., Rahbar, Ramtin, Fish, Eleanor N.
Format: Article
Language:English
Subjects:
60 APPLIED LIFE SCIENCES
Apoptosis Regulatory Proteins - biosynthesis
Breast Neoplasms - metabolism
Breast Neoplasms - pathology
Cell Line, Tumor
CELL PROLIFERATION
Chemokine
Chemokine CCL5 - genetics
Chemokine CCL5 - metabolism
Cyclin D1 - biosynthesis
Eukaryotic Initiation Factor-4F - metabolism
Female
GENE REGULATION
Humans
LIGANDS
MAMMARY GLANDS
Membrane Proteins - biosynthesis
MESSENGER-RNA
MOLECULAR WEIGHT
NEOPLASMS
Polyribosomes - metabolism
Proliferation
Protein Biosynthesis
Protein Kinases - metabolism
Proto-Oncogene Proteins c-myc - biosynthesis
RECEPTORS
Receptors, CCR5 - metabolism
RNA, Messenger - metabolism
Signal transduction
TOR Serine-Threonine Kinases
Translation
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Summary:The proliferative capacity of cancer cells is regulated by factors intrinsic to cancer cells and by secreted factors in the microenvironment. Here, we investigated the proto-oncogenic potential of the chemokine receptor, CCR5, in MCF-7 breast cancer cell lines. At physiological levels, CCL5, a ligand for CCR5, enhanced MCF-7.CCR5 proliferation. Treatment with the mTOR inhibitor, rapamycin, inhibited this CCL5-inducible proliferation. Because mTOR directly modulates mRNA translation, we investigated whether CCL5 activation of CCR5 leads to increased translation. CCL5 induced the formation of the eIF4F translation initiation complex through an mTOR-dependent process. Indeed, CCL5 initiated mRNA translation, shown by an increase in high-molecular-weight polysomes. Specifically, we show that CCL5 mediated a rapid up-regulation of protein expression for cyclin D1, c-Myc and Dad-1, without affecting their mRNA levels. Taken together, we describe a mechanism by which CCL5 influences translation of rapamycin-sensitive mRNAs, thereby providing CCR5-positive breast cancer cells with a proliferative advantage.
ISSN:0006-291X
1090-2104
DOI:10.1016/j.bbrc.2009.07.035