Inhibitory effects of somatostatin on rat hepatocyte proliferation are mediated by cyclic AMP

Abstract

Somatostatin (SS-14) is known as an antigrowth factor for a variety of cell types, including gastrointestinal mucosa, exocrine pancreas, lymphocytes, and some tumors. We have recently identified and biochemically characterized SS-14-binding protein on rat liver plasma membranes (S. E. Raper, P. C. Kothary, and J. DelValle, Gastroenterology 96: A408, 1989; P. C. Kothary et al., Digestion 46 (Suppl 1): 58, 1990). We hypothesized that SS-14 may affect liver growth as well and investigated cellular mechanisms of this phenomenon focusing on the second messenger cAMP. Freshly isolated rat hepatocytes were plated on tissue culture dishes coated with Matrigel (laminin, heparan sulfate, and type IV collagen). The medium was not supplemented with serum or hormones. Either dibutyryl-cAMP (1 mM) or isobutylmethylxanthine (IBMX, 0.1 mM) was added in the presence or absence of SS-14 (10 nM). DNA synthesis was estimated by the rate of [3H]thymidine incorporation into DNA and by the labeling index (an autoradiographic measurement of the number of labeled nuclei). SS-14 significantly inhibited both [3H]thymidine incorporation and labeling index of rat hepatocytes stimulated by dibutyryl-cAMP or IBMX. SS-14 also inhibited intracellular cAMP accumulation stimulated by IBMX. We conclude that SS-14 exerts at least part of its antiproliferative effects via the adenylate cyclase system. Further study using other signal transduction systems may yield more information about mechanisms of hepatocyte growth.

Preferential suppression of insulin‐stimulated proliferation of cultured hepatocytes by somatostatin: Evidence for receptor‐mediated growth regulation

“…Second messenger systems participate in the regulation of cellular proliferation [Dumont et al, 19891. The adenylate cyclase system is a well known second messenger system that has been postulated to play a major role in the cell proliferation [Ha-segwa et al, 1980;Kokudo et al, 1991;Raper et al, 1991bI. In addition, the SS-14 receptor is shown to be coupled to the adenylyl cyclase system in several types of cells [Reisine arid Gould, 19891. Our studies show that there is a n increase in intracellular CAMP synthesis during liver regeneration (Table 11).…”

Somatostatin analog SMS 201995 inhibits proliferation in human leukemia T-cell line: Relevance of the adenylyl cyclase stimulation

“…Nevertheless, SRIF14 not only stimulates the proliferation of T cells [Nordlind and Mutt, 1985;Nordlind and Mutt, 1986;Johansson and Sandberg, 1989] as it would be expected based on its capacity to inhibit cAMP-PKA pathway [Kammer, 1988], but is also able to inhibit it [Payan et al, 1984;Pawlikowski et al, 1985;Nio et al, 1993]. Similarly, in other cell types, both SRIF14-dependent positive [Johansson and Madsen, 1987] and negative [Tsuzaki and Moses, 1990;Kokudo et al, 1991] regulation of proliferation has been documented. By contrast, a metabolically stable SRIF14 analog, octreotide SMS 201995, inhibits cell proliferation in almost all cell types studied [Feindt et al, 1997;Pawlikowski et al, 1997a;Pawlikowski et al, 1997b;Yumi et al, 1997;Feindt et al, 1998] including normal human T lymphocytes [Malec et al, 1989;Atiya et al, 1997].…”

Inhibition of DNA synthesis by somatostatin in rat hepatocytes stimulated by hepatocyte growth factor or epidermal growth factor

“…Somatostatin is known to inhibit the growth of a number of cell types such as gastrointestinal mucosa [ZO], exocrine pancreas [ 1 I 1, lymphocytes [ 121, and some tumors [13]. We have recently shown that somatostatin inhibits DNA synthesis in rat hepatocytes stimulated by insulin or CAMP analogue [14,15] and that the liver takes up intraportally injected somatostatin-14 in an eflicient and saturable manner [16]. These findings, taken together with the fact that immunoreactive somatostatin levels measured in the portal vein are 10 times higher than in systemic circulation [ 171, have led us to hypothesize that somatostatin may play an important role in regulating liver regeneration.…”