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 la-myristate 13-acetate (PMA) transien tly reduced the level of EGF receptor tyrosine phosphorylation in three pan creatic cancer cell lines (HPAC, SW1990, and UCVA-1) in response to EGF. Th e effect was maximal at 40-90 min. Pretreatment with the protein kinase C i nhibitor GF 109203X reduced the PMA effect. Flow cytometry experiments show ed that PMA produced only a slight reduction in the surface expression of E GF-R. The phosphotyrosine phosphatase inhibitor bpV(phen) returned phosphor ylation to almost control levels. Moreover, homogenates of PMA treated panc reatic cells reduced the phosphorylation of activated receptor that was imm unoprecipitated 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 red uces the steady-state level of tyrosine phosphorylation of the receptor tha t is induced by EGF. (C) 1999 Academic Press.