Protein kinase C desensitization by phorbol esters and its impact on growth of human breast cancer cells.
Active phorbol esters such as TPA (12-0-tetra-decanoylphorbol-13-acetate) inhibited growth of mammary carcinoma cells (MCF-7 greater than BT-20 greater than MDA-MB-231 greater than = ZR-75-1 greater than HBL-100) with the exception of T-47-D cells presumably by interacting with the phospholipid/Ca2+-dependent protein kinase (PKC). The nonresponsive T-47-D cells exhibited the lowest PKC activity. A rapid (30 min) TPA-dependent translocation of cytosolic PKC to membranes was found in the five TPA-sensitive cell without affecting cell growth. However, TPA-treatment of more than 10 hours inhibited reversibly the growth of TPA-responsive cells. This effect coincided with the complete loss of cellular PKC activity due to the proteolysis of the translocated membrane-bound PKC holoenzyme (75K) into 60K and 50K PKC fragments. Resumption of cell growth after TPA-removal was closely related to the specific reappearance of the PKC holoenzyme activity (75K) in the TPA-responsive human mammary tumor cell lines suggesting an involvement of PKC in growth regulation.
D001943:Breast Neoplasms / Q000201:enzymology*; D002451:Cell Compartmentation; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D003600:Cytosol / Q000201:enzymology; D005260:Female; D006131:Growth Inhibitors; D006801:Humans; D008566:Membranes / Q000201:enzymology; D010447:Peptide Hydrolases / Q000378:metabolism; D010703:Phorbol Esters / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism; D013997:Time Factors
D006131:Growth Inhibitors; D010703:Phorbol Esters; D011494:Protein Kinases; D011493:Protein Kinase C; D010447:Peptide Hydrolases