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Laboratory of Molecular Oncology and Cell Cycle Regulation, University of Pennsylvania Comprehensive Cancer Center, Howard Hughes Medical Institute, Department of Medicine and Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104
Growth arrest and differentiation of leukemic cells by phorbol 12-myristate 13-acetate (PMA) is accompanied by p53-independent activation of p21WAF1/CIP1 and c-myc down-regulation. We show that despite p21 induction in 7 of 12 human cancer cell lines treated with PMA, growth inhibition was observed only in two cell lines (SKBr3 breast and LNCaP prostate cancer cells). Treatment of SKBr3 and LNCaP cells with PMA was followed by Raf-1 hyperphosphorylation, p21 induction, Rb hypophosphorylation, c-myc down-regulation and growth inhibition. The 10 remaining PMA-resistant cell lines were comprised of 5 that failed to induce p21 and 5 that induced p21 but had defects in steps putatively downstream of this (Rb hypophosphorylation and c-myc down-regulation). Exogenous expression and subsequent failure to down-regulate c-myc protein expression in SKBr3 and LNCaP cells was correlated with acquisition of resistance to the growth inhibitory effect of PMA. Exogenous p21 expression down-regulated c-myc protein in PMA-sensitive cancer cells. Our findings suggest that induction of p21 and down-regulation of c-myc may be necessary steps in a PMA-induced growth-inhibitory pathway in cancer cells.
1 Assistant Investigator of the Howard Hughes Medical Institute and to whom requests for reprints should be addressed, at Howard Hughes Medical Institute Research Labs, University of Pennsylvania School of Medicine, Clinic Research Building, Room 437A, 415 Curie Blvd., Philadelphia, PA 19104-6148. Fax: (215) 573-9139.
Received 3/ 7/96. Accepted 11/12/96.
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