Ishizuka J, Beauchamp R D, Sato K, Townsend C M, Thompson J C
Department of Surgery, University of Texas Medical Branch, Galveston 77555-0533.
J Cell Physiol. 1993 Jul;156(1):112-8. doi: 10.1002/jcp.1041560116.
We have shown recently that 5-HT is an autocrine growth stimulatory factor for a cell line (BON) that is derived from a human pancreatic carcinoid tumor. This action is mediated by a 5-HT receptor-linked decrease of cyclic adenosine monophosphate (AMP) production, but not mediated by a 5-HT receptor-linked stimulation of phosphatidylinositol hydrolysis. The BON cells also express transforming growth factor betas (TGF beta s) (1, 2, and 3) and release TGF beta into their medium. In this study, we examined the effects of TGF beta on the secretion of 5-HT, on signal transduction pathways involved in 5-HT secretion, and on growth of BON cells. TGF beta 1 inhibited basal and acetylcholine-stimulated release of 5-HT, but did not inhibit isobutylmethylxanthine-stimulated release of 5-HT. TGF beta 1 inhibited both basal and acetylcholine-stimulated hydrolysis of phosphatidylinositol in a dose dependent manner, but did not affect cyclic AMP production. TGF-beta 1 inhibited growth of BON cells in culture; this effect was reversed by exogenously administered 5-HT. Three different specific and saturable TGF beta 1 binding sites were identified; binding assays performed after mild acid wash (0.1% acetic acid, pH 2.5) conditions uncovered TGF beta receptors that were apparently occupied by endogenously produced TGF beta species. Affinity cross-linking assay showed that BON cells had three different TGF beta binding proteins. These results suggest that TGF beta 1 can inhibit growth of BON cells by altering secretory responses of 5-HT by means of receptor-mediated inhibition of phosphatidylinositol hydrolysis. We conclude that growth of BON cells is regulated, at least in part, by the opposing receptor-mediated autocrine actions of 5-HT and TGF beta.
我们最近发现，5-羟色胺（5-HT）是一种源自人类胰腺类癌肿瘤的细胞系（BON）的自分泌生长刺激因子。这一作用是由5-HT受体介导的环磷酸腺苷（AMP）生成减少介导的，而非由5-HT受体介导的磷脂酰肌醇水解刺激介导。BON细胞还表达转化生长因子β（TGFβ）（1、2和3），并将TGFβ释放到培养基中。在本研究中，我们研究了TGFβ对5-HT分泌、5-HT分泌所涉及的信号转导途径以及BON细胞生长的影响。TGFβ1抑制基础和乙酰胆碱刺激的5-HT释放，但不抑制异丁基甲基黄嘌呤刺激的5-HT释放。TGFβ1以剂量依赖方式抑制基础和乙酰胆碱刺激的磷脂酰肌醇水解，但不影响环AMP生成。TGF-β1抑制培养的BON细胞生长；外源性给予5-HT可逆转这一作用。鉴定出三种不同的特异性和可饱和的TGFβ1结合位点；在轻度酸洗（0.1%乙酸，pH 2.5）条件下进行的结合试验发现了明显被内源性产生的TGFβ种类占据的TGFβ受体。亲和交联试验表明BON细胞有三种不同的TGFβ结合蛋白。这些结果表明，TGFβ1可通过受体介导的磷脂酰肌醇水解抑制来改变5-HT的分泌反应，从而抑制BON细胞生长。我们得出结论，BON细胞的生长至少部分受5-HT和TGFβ相反的受体介导的自分泌作用调节。
