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 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.
Murooka
Thomas T
TT
Division of Cellular and Molecular Biology, Toronto General Research Institute, University Health Network, Ont, Canada.
Rahbar
Ramtin
R
Fish
Eleanor N
EN
D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018946:Chemokine CCL5 / Q000235:genetics / Q000378:metabolism*; D019938:Cyclin D1 / Q000096:biosynthesis; D039562:Eukaryotic Initiation Factor-4F / Q000378:metabolism; D005260:Female; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis; D011132:Polyribosomes / Q000378:metabolism; D014176:Protein Biosynthesis; D011494:Protein Kinases / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis; D012333:RNA, Messenger / Q000378:metabolism*; D019713:Receptors, CCR5 / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases
D051017:Apoptosis Regulatory Proteins; C483024:CCL5 protein, human; D018946:Chemokine CCL5; C083331:DAD1 protein, human; D039562:Eukaryotic Initiation Factor-4F; C489427:MYC protein, human; D008565:Membrane Proteins; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D019713:Receptors, CCR5; D019938:Cyclin D1; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases