SIGNAL TRANSDUCTION EVENTS AND THE REGULATION OF CELL GROWTH

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This project is designed to increase our understanding of the biology of prostate cancer and to develop a new approach to the treatment of advanced prostatic cancer through the study of the signal transduction events regulating the growth of human prostate carcinoma cell lines. This work is currently focused on (1)the anticancer activity of HMG-CoA reductase inhibitor lovastatin, and (2)the role of heterotrimeric G proteins in malignant transformation and the molecular mechanisms regulating G protein expression. We have found that lovastatin treatment markedly alters the subcellular distribution of critical growth-regulatory gene products, including c-myc and the retinoblastoma protein, and that this redistribution is associated with shifts in the balance of protein phosphorylation and O-linked glycosylation. The data suggest that drugs of this class may be used to interrupt nuclear oncoprotein function, Studies of the G protein phenotype of prostate cancer cells showed that hormone-refractory cells express abundant membrane-associated G alpha 12, alpha l3, alpha il,2, and alphaz, in marked contrast to hormone-sensitive cells that have no detectable membrane-associated protein. This is particularly important in light of recent studies implicating G alpha subunits in malignant transformation. Hormone-sensitive cells were found to transcribe and translate alpha subunits but not insert them in the plasma membrane. Protein myristoylation is believed to be important in the tethering of signalling molecules including G alpha subunits and src to the plasma membrane. We found that hormone-sensitive cells had almost undetectable levels of the message encoding N-myristoyltransferase, the enzyme that catalyzes protein N-myristoylation, and that total cellular myristoylation was almost undetectable, in contrast to the androgen- independent cells in which both mRNA for the acylating enzyme and total cellular myristoylated protein were readily detectable.