Expression of activin A and its receptors in human pheochromocytomas

Activin A (a homodimer of two activin beta A subunits) has been shown to induce the neuronal differentiation of rat pheochromocytoma PC12 cells. We studied activin A and its receptor gene expression in human pheochromocytomas in vivo and in vitro to clarify the potential involvement of activin A in the pathophysiology of these tumors. We first screened 20 pheochromocytomas and nine normal adrenal tissues for activin beta A mRNA expression. Northern blots hybridized with specific oligonucleotide probes detected weak signals for activin beta A transcripts in pheochromocytomas. Both type I and type II activin receptor (ActR-I, ActR-IB and ActR-II) mRNA expression was also detectable in the pheochromocytoma tissues. In primary cultures of pheochromocytoma cells, expression of activin beta A mRNA was readily detectable by Northern blotting, and secretion of activin A into the conditioned medium was confirmed by an enzyme-linked immunosorbent assay. The expression of activin beta A mRNA and secretion of activin A were induced by (Bu)(2)cAMP after 1 and 3 days of treatment (all P<0.05). A protein kinase inhibitor, staurosporine, inhibited the basal and (Bu)(2)cAMP-induced accumulation of activin beta A mRNA (P<0.05). In addition, induction of chromaffin phenotype by dexamethasone also inhibited the basal and (Bu)(2)cAMP-induced expression of activin A at both mRNA and protein levels (all P<0.05). In contrast, the expression of ActR-I and ActR-IB mRNAs was not affected by these agents in cultured pheochromocytoma cells. In summary, activin beta A subunit and activin receptors are expressed in human pheochromocytomas. Production of activin A in cultured pheochromocytoma cells is induced through the protein kinase A pathway, but reduced during chromaffin differentiation. Therefore, activin A may function as a local neurotrophic factor via an auto/paracrine manner in human pheochromocytomas.