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cAMP and protein kinase A in endocrine (and other) tumors

Studies of the biological role of cAMP have indicated dual and often opposing effects on proliferation and differentiation. Elevation of the intracellular cAMP in normal and transformed cells may lead to cell proliferation; in other cells, it induces changes in morphology, apoptosis and/or differentiation. The best known mediator of cAMP action in the cell is cAMP-dependent protein kinase or protein kinase A (PKA). PKA exists as two different isozymes, designated type I (PKA-I) and type II (PKA-II); the two isoforms are essentially distinct in their physicochemical properties. The relative ratio of PKA-I and PKA-II varies throughout the cell cycle in cells of the same type, it changes significantly during development and follows different patterns in the various tissues. Disruption of the apparently fine balance between the main two PKA isozymes is strongly associated with tumorigenesis and tumor growth, and vice versa. The enormous variety of cAMP/PKA functions and the net effect of this signaling system on cellular growth, proliferation and differentiation have been the subject of debate for more than 30 years among investigators in the field. The relatively recent identification of PRKAR1A mutations and PKA-I deficiency as a cause of endocrine and other tumors in human and mice was instrumental in advancing our understanding of how cAMP and PKA work in regulating the cell cycle. This article reviews the current state of knowledge in the field; the use of pharmacologic modulation of the cAMP/PKA system with the goal of treating certain tumors appears to be near, although very little has been accomplished so far, at least in terms of studies on humans.