DEFECTS IN P21(WAF1 CIP1), RB, AND C-MYC SIGNALING IN PHORBOL ESTER-RESISTANCE CANCER-CELLS/

Growth arrest and differentiation of leukemic cells by phorbol 12-myri state 13-acetate (PMA) is accompanied by p53-independent activation of p21(WAF1/CIP1) and c-myc down-regulation. We show that despite p21 in duction in 7 of 12 human cancer cell lines treated with PMA, growth in hibition was observed only in two cell lines (SKBr3 breast and LNCaP p rostate cancer cells), Treatment of SKBr3 and LNCaP cells with PMA was followed by Raf-l hyperphosphorylation, p21 induction, Rb hypophospho rylation, c-myc down-regulation and growth inhibition, The 10 remainin g PMA-resistant cell lines were comprised of 5 that failed to induce p 21 and 5 that induced p21 but had defects in steps putatively downstre am of this (Rb hypophosphorylation and c-myc down-regulation), Exogeno us expression and subsequent failure to down-regulate c-myc protein ex pression in SKBr3 and LNCaP cells was correlated with acquisition of r esistance to the growth inhibitory effect of PMA. Exogenous p21 expres sion down-regulated c-myc protein in PMA-sensitive cancer cells, Our f indings suggest that induction of p21 and down-regulation of c-myc may be necessary steps in a PMA-induced growth-inhibitory pathway in canc er cells.