COUNTERACTIONS OF RETINOIC ACID AND PHORBOL ESTER TUMOR PROMOTER RELATED TO CHANGES IN PROTEIN KINASE ACTIVITIES

Retinoids, derivatives of vitamin A, are antagonistic toward some of the actions of phorbol ester tumor promoters (TPA) in many cell systems, and may be important as agents in cancer chemotherapy and prevention. We have been involved with studies to elucidate the effects and counteractions of retinoic acid (RA) and TPA on two key protein kinase systems known to play a role in the regulation of cell growth, differentiation, and malignant transformation: protein kinase C (PKC) and cyclic AMP-dependent protein kinase (PKA). Results indicate that RA treatment of cells causes marked changes in PKA activity, and in the PKA regulatory subunits RI and RII, and suggest an important synergism between RA and cyclic AMP to regulate cell growth and differentiation. Treatment of cells with TPA induces a rapid activation of PKC at the plasma membrane. Within 10 min TPA also causes an increase in PKA activity, and in RI and RII, in the cytosol of PYS cells. RA, when added simultaneously with TPA, negates this TPA effect on PKA. Further, prolonged TPA treatment of cells results in a loss of PKC, whereas prolonged RA treatment of some undifferentiated cell types elevates PKC activity in the cytosol. Thus, RA and TPA can elicit opposite and antagonistic effects on PKA and PKC. These changes in protein kinase activities may be involved in the antineoplastic and therapeutic actions of retinoids.