TGF-β1-ROS-ATM-CREB signaling axis in macrophage mediated migration of human breast cancer MCF7 cells.
Macrophages in the tumor microenvironment play an important role in tumor cell survival. They influence the tumor cell to proliferate, invade into surrounding normal tissues and metastasize to local and distant sites. In this study, we evaluated the effect of conditioned medium from monocytes and macrophages on growth and migration of breast cancer cells. Macrophage conditioned medium (MϕCM) containing elevated levels of cytokines TNF-α, IL-1β and IL-6 had a differential effect on non-invasive (MCF7) and highly invasive (MDA-MB-231) breast cancer cell lines. MϕCM induced the secretion of TGF-β1 in MCF7 cells. This was associated with apoptosis in a fraction of cells and generation of reactive oxygen and nitrogen species (ROS and RNS) and DNA damage in the remaining cells. This, in turn, increased expression of cAMP response element binding protein (CREB) and vimentin resulting in migration of cells. These effects were inhibited by neutralization of TNF-α, IL-1β and IL-6, inhibition of ROS and RNS, DNA damage and siRNA mediated knockdown of ATM. In contrast, MDA-MB-231 cells which had higher basal levels of pCREB were not affected by MϕCM. In summary, we have found that pro-inflammatory cytokines secreted by macrophages induce TGF-β1 in tumor cells, which activate pCREB signaling, epithelial-mesenchymal-transition (EMT) responses and enhanced migration.
Radiation Biology & Health Sciences Division, Bio-Science Group, Bhabha Atomic Research Centre, Mumbai 400 085, India.
Rajshri
R
Singh
Radiation Biology & Health Sciences Division, Bio-Science Group, Bhabha Atomic Research Centre, Mumbai 400 085, India. Electronic address: bshankar@barc.gov.in.
Bhavani S
BS
Shankar
Radiation Biology & Health Sciences Division, Bio-Science Group, Bhabha Atomic Research Centre, Mumbai 400 085, India.
Krishna B
KB
Sainis
D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D017209:Apoptosis / Q000276:immunology; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival; D017077:Culture Media, Conditioned / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000096:biosynthesis / Q000378:metabolism*; D004249:DNA Damage / Q000276:immunology; D058750:Epithelial-Mesenchymal Transition / Q000276:immunology*; D005260:Female; D006801:Humans; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology; D061986:MCF-7 Cells; D008264:Macrophages / Q000276:immunology*; D009000:Monocytes / Q000276:immunology; D034622:RNA Interference; D034741:RNA, Small Interfering; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D059016:Tumor Microenvironment / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000276:immunology; D014746:Vimentin / Q000096:biosynthesis; D000093242:Interleukin-6 Inhibitors
D000906:Antibodies; D064007:Ataxia Telangiectasia Mutated Proteins; D017077:Culture Media, Conditioned; D017362:Cyclic AMP Response Element-Binding Protein; D053583:Interleukin-1beta; D015850:Interleukin-6; D034741:RNA, Small Interfering; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D014746:Vimentin; D000093242:Interleukin-6 Inhibitors; C115163:CREB1 protein, human; C576324:ATM protein, human
CREB; DNA damage; EMT; Macrophage; Oxidative stress; TGF-β1