Adherence to osteopontin via alphavbeta3 suppresses phorbol ester-mediated apoptosis in MCF-7 breast cancer cells that overexpress protein kinase C-alpha.
Overexpression of protein kinase C-alpha in MCF-7 breast cancer cells (MCF-7-PKC-alpha cells) results in anchorage-independent growth and increased tumorigenicity of these cells in nude mice. MCF-7-PKC-alpha cells, unlike their parental MCF-7 cells, are sensitized to apoptosis by phorbol esters. When adhered to osteopontin, a bone matrix protein, MCF-7-PKC-alpha cells were resistant to phorbol ester mediated apoptosis. Fluorescence-activated cell sorting revealed that osteopontin receptors, alphavbeta3 and alphavbeta5, are expressed on MCF-7-PKC-alpha cells and that both are used to adhere to osteopontin. Addition of an RGD-containing peptide inhibited survival of MCF-7-PKC-alpha cells exposed to phorbol ester and adhered to osteopontin. This indicated that an integrin was involved in the cell death suppression signal. Whereas, anti-alphavbeta5 antibody did not reduce survival of MCF-7-PKC-alpha cells adhered to osteopontin, anti-alphavbeta3 antibody could efficiently block suppression of apoptosis. Phorbol ester also induced increased expression of alphavbeta3 on MCF-7-PKC-alpha cells by upregulating expression of a second species of beta3 mRNA. This study suggests that breast cancer cells that have metastasized to bone may have a survival advantage resulting from interaction of alphavbeta3 on these cells with the bone protein osteopontin.
Noti
J D
JD
Laboratory of Molecular Biology, Guthrie Research Institute, One Guthrie Square, Sayre, PA 18840, USA. jnoti@inet.guthrie.org
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics; D017209:Apoptosis / Q000187:drug effects*; D001859:Bone Neoplasms / Q000556:secondary; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects; D004790:Enzyme Induction; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D039661:Integrin beta3; D007527:Isoenzymes / Q000096:biosynthesis* / Q000235:genetics; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D053495:Osteopontin; D010980:Platelet Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics; D011493:Protein Kinase C / Q000096:biosynthesis* / Q000235:genetics; D051571:Protein Kinase C-alpha; D019030:Receptors, Vitronectin / Q000235:genetics / Q000378:metabolism*; D012795:Sialoglycoproteins / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D015703:Antigens, CD; D016326:Extracellular Matrix Proteins; D039661:Integrin beta3; D007527:Isoenzymes; D009363:Neoplasm Proteins; D009842:Oligopeptides; D010980:Platelet Membrane Glycoproteins; D019030:Receptors, Vitronectin; C506895:SPP1 protein, human; D012795:Sialoglycoproteins; D053495:Osteopontin; C047981:arginyl-glycyl-aspartic acid; C496628:PRKCA protein, human; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D013755:Tetradecanoylphorbol Acetate