Phorbol ester reduces phosphorylation of epidermal growth factor receptor in pancreatic cancer cells by activation of a tyrosine phosphatase.
In this study we report that phorbol 12-myristate 13-acetate (PMA) transiently reduced the level of EGF receptor tyrosine phosphorylation in three pancreatic cancer cell lines (HPAC, SW1990, and UCVA-1) in response to EGF. The effect was maximal at 40-90 min. Pretreatment with the protein kinase C inhibitor GF 109203X reduced the PMA effect. Flow cytometry experiments showed that PMA produced only a slight reduction in the surface expression of EGF-R. The phosphotyrosine phosphatase inhibitor bpV(phen) returned phosphorylation to almost control levels. Moreover, homogenates of PMA treated pancreatic cells reduced the phosphorylation of activated receptor that was immunoprecipitated from A431 epidermoid cells. A combination of orthovanadate and NaF or bpV(phen) inhibited the effect of the homogenates. These results suggest that PMA activates a phosphotyrosine phosphatase activity that reduces the steady-state level of tyrosine phosphorylation of the receptor that is induced by EGF.
Ho
J J
JJ
Veterans Medical Center, University of California, San Francisco, California, 94121, USA. jjl@itsa.ucsf.edu
Farrelly
E R
ER
Kim
Y S
YS
D002462:Cell Membrane / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D009942:Organometallic Compounds / Q000494:pharmacology; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D010618:Phenanthrolines / Q000494:pharmacology; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011799:Quinazolines; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D020032:Tyrphostins / Q000494:pharmacology
D004791:Enzyme Inhibitors; D009942:Organometallic Compounds; D010618:Phenanthrolines; D011799:Quinazolines; D020032:Tyrphostins; C101044:RTKI cpd; C102120:bisperoxo(1,10-phenanthroline)oxovanadate(1-); D066246:ErbB Receptors; D017027:Protein Tyrosine Phosphatases; D013755:Tetradecanoylphorbol Acetate