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Atypical Protein Kinase C Suppresses Migration of Mouse Melanoma Cells¹

Department of Chemistry and Biochemistry [E. S-N., S. A. R.] and Graduate Center [E. S-N.], Queens College of the City University of New York, Flushing, New York 11367, and Center for Experimental Therapeutics and Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania [N. F., M. G. K.]

Mouse melanoma B16 F1 cells cultured in RPMI 1640 supplemented with the melanin precursors tyrosine and phenylalanine display increased melanin levels and elevated migration while down-regulating protein kinase C (PKC) to low levels. Although control experiments rule out a direct role by melanin, PKC down-regulation is shown to be a critical determinant of cell migration. Transfection of high-motility cells with either wild-type PKC or its regulatory domain suppresses migration. Known to bind to the regulatory domain of PKC, the proapoptotic protein prostate apoptosis response-4 (Par-4) coimmunoprecipitates with PKC as a 47-kDa protein. Transfection of Par-4 (or its leucine zipper element) further suppresses migration of low-motility cells (which express high levels of PKC), whereas high-motility cells (which express low levels of PKC) are unaffected by Par-4 overexpression. It is proposed that in nonmetastatic cells, the PKC Par-4 complex provides a brake on migration that is released by melanin precursors that initiate PKC down-regulation. Elevation of PKC in melanoma cells, or preventing its down-regulation through the dietary restriction of tyrosine and phenylalanine, may therefore control metastatic behavior.

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				P. RANGANATHAN and V. M. RANGNEKAR Regulation of Cancer Cell Survival by Par-4 Ann. N.Y. Acad. Sci., November 1, 2005; 1059(1): 76 - 85. [Abstract] [Full Text] [PDF]