A polyamine pathway-mediated mitogenic mechanism in enterochromaffin-like cells of Mastomys.
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.
Gastrointestinal Surgical Pathobiology Research Group, Yale University School of Medicine and the West Haven Veterans Affairs Medical Center, New Haven, Connecticut 06520-8062, USA.
M
M
Kidd
L H
LH
Tang
S W
SW
Schmid
K
K
Miu
I M
IM
Modlin
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D000518:Eflornithine / Q000494:pharmacology*; D019861:Enterochromaffin-like Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D005753:Gastric Mucosa / Q000166:cytology / Q000502:physiology*; D005755:Gastrins / Q000494:pharmacology / Q000502:physiology; D009115:Muridae; D009955:Ornithine Decarboxylase / Q000378:metabolism*; D011073:Polyamines / Q000378:metabolism* / Q000494:pharmacology; D011700:Putrescine / Q000378:metabolism; D013095:Spermidine / Q000378:metabolism; D013096:Spermine / Q000378:metabolism; D016211:Transforming Growth Factor alpha / Q000494:pharmacology / Q000502:physiology
D005755:Gastrins; D011073:Polyamines; D016211:Transforming Growth Factor alpha; D013096:Spermine; D004247:DNA; D009955:Ornithine Decarboxylase; D013095:Spermidine; D011700:Putrescine; D000518:Eflornithine