Kidd M, Tang L H, Schmid S W, Miu K, Modlin I M
Gastrointestinal Surgical Pathobiology Research Group, Yale University School of Medicine and the West Haven Veterans Affairs Medical Center, New Haven, Connecticut 06520-8062, USA.
Am J Physiol. 1998 Aug;275(2):G370-6. doi: 10.1152/ajpgi.1998.275.2.G370.
We have previously demonstrated that in Mastomys species proliferation of gastric enterochromaffin-like (ECL) cells is predominantly regulated by gastrin and by transforming growth factor-alpha (TGF-alpha) in the naive and neoplastic state, respectively. In this study we examined whether these intracellular mitogenic responses are mediated by polyamines and ornithine decarboxylase (ODC), the rate-limiting enzyme for polyamine biosynthesis. An ECL cell preparation of high purity was used to measure the effect of the polyamine derivatives putrescine, spermidine, and spermine on DNA synthesis by bromodeoxyuridine uptake. Both putrescine and spermidine augmented gastrin-stimulated, but not basal, DNA synthesis in naive cells. This proliferative response correlated with an increase in ODC activity that was partially inhibited (20%) by difluoromethylornithine (DFMO), an inhibitor of ODC (IC50, 30 pM). In contrast, all polyamines increased both basal and TGF-alpha-stimulated DNA synthesis as well as ODC activity in tumor ECL cells. DFMO completely inhibited the proliferative response of TGF-alpha (IC50, 3 pM). Thus polyamine biosynthesis is involved in proliferation of ECL cells and in particular the mitogenesis of tumor cells, suggesting a role for this pathway in the regulation of ECL cell transformation.
我们之前已经证明，在多乳鼠属物种中，胃肠嗜铬样（ECL）细胞的增殖在幼稚状态和肿瘤状态下分别主要受胃泌素和转化生长因子-α（TGF-α）调节。在本研究中，我们检测了这些细胞内的促有丝分裂反应是否由多胺和鸟氨酸脱羧酶（ODC）介导，ODC是多胺生物合成的限速酶。使用高纯度的ECL细胞制剂，通过溴脱氧尿苷摄取来测量多胺衍生物腐胺、亚精胺和精胺对DNA合成的影响。腐胺和亚精胺均增强了幼稚细胞中胃泌素刺激的而非基础的DNA合成。这种增殖反应与ODC活性的增加相关，ODC活性的增加被ODC抑制剂二氟甲基鸟氨酸（DFMO）部分抑制（20%）（IC50，30 pM）。相反，所有多胺均增加了肿瘤ECL细胞的基础和TGF-α刺激的DNA合成以及ODC活性。DFMO完全抑制了TGF-α的增殖反应（IC50，3 pM）。因此，多胺生物合成参与ECL细胞的增殖，尤其是肿瘤细胞的有丝分裂，表明该途径在ECL细胞转化的调节中起作用。
