title: TNF-α renders macrophages resistant to a range of cancer chemotherapeutic agents through NF-κB-mediated antagonism of apoptosis signalling.
abstract: The abundance of macrophages is an independent negative prognostic factor in a range of cancer types, linked to the actions of macrophage products on vasculogenesis and cancer cell survival, motility and metastasis. TNF-α is a macrophage product and a product of some cancer cell types that is also associated with adverse prognosis in clinical and experimental cancers, through enhanced tumour cell growth, survival and metastasis. Macrophages are important targets of TNF-α. We observed that TNF-α partly substituted for the macrophage growth factor, M-CSF, in maintaining macrophage survival by protecting cells from apoptosis. We found that TNF-α afforded similar protection to chemotherapeutic agents and related cytotoxic drugs that acted through a range of apoptosis-initiating pathways, but not where protein synthesis was inhibited. Protection was dependent on intact NF-κB signalling. In addition to NF-κB-dependent factors previously identified as anti-apoptotic, we found an absolute requirement for very early antagonism of mitochondrial cytochrome C release, which sufficed to prevent apoptosis in the face of activation of a range of upstream apoptosis pathways, including p53, DISC-linked, mitochondrial depolarisation and calcium-sensitive pathways. The capacity of TNF-α to preserve macrophage numbers in the face of chemotherapy drugs is a potential contributor to prognosis in TNF-α-expressing cancers, encouraging further testing of anti-TNF-α treatments in these patients.
authors.affiliation: Pharmacology Unit, School of Medicine & Pharmacology, University of Western Australia, 35 Stirling Highway, Crawley, Western Australia 6009, Australia. Electronic address: Susan.Lo@uwa.edu.au.
authors.forename: Susan Z Y
authors.initials: SZY
authors.lastname: Lo
authors.affiliation: Pharmacology Unit, School of Medicine & Pharmacology, University of Western Australia, 35 Stirling Highway, Crawley, Western Australia 6009, Australia.
authors.forename: James H
authors.initials: JH
authors.lastname: Steer
authors.affiliation: Pharmacology Unit, School of Medicine & Pharmacology, University of Western Australia, 35 Stirling Highway, Crawley, Western Australia 6009, Australia.
authors.forename: David A
authors.initials: DA
authors.lastname: Joyce
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D004359:Drug Therapy, Combination; D005260:Female; D005434:Flow Cytometry; D008264:Macrophages / Q000166:cytology / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects; D000083162:Mitochondrial Permeability Transition Pore; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D016328:NF-kappa B; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D047888:Receptors, Tumor Necrosis Factor, Type I; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha; D000255:Adenosine Triphosphate; D045304:Cytochromes c; D002118:Calcium