Evidence for control of nitric oxide synthesis by intracellular transforming growth factor-beta1 in tumor cells. Implications for tumor development.
Transforming growth factor-beta1 (TGF-beta1) has been shown to down-regulate NO synthesis in a variety of normal cells. In the present study, we investigated the influence of TGF-beta1 upon NO production in tumor cells and its consequences for tumor development. During the growth of PROb colon carcinoma cells intraperitoneally injected in syngeneic BDIX rats, intratumoral concentration of TGF-beta1 increases while NO concentration stays very low. Tumor regression induced by intraperitoneal injections of a lipid A is associated with a decrease in TGF-beta1 and an increase in NO intratumoral concentration. In these tumors, PROb tumor cells are the NO- and TGF-beta1-secreting cells. Using PROb cells transfected with an expression vector coding for TGF-beta1 antisense mRNA, we demonstrate in vitro that there is an inverse correlation between the amount of TGF-beta1 secreted and the ability of PROb cells to secrete NO. As the same results were obtained in the presence of an anti-TGF-beta type II receptor neutralizing antibody, and as exogenous TGF-beta1 is without any effect on NO secretion by PROb cells, TGF-beta1 apparently down-regulates NO synthesis in PROb cells by an intracellular mechanism. These results suggest that endogenous TGF-beta1 constitutes a potential target in a search for new antitumoral agents.
Lagadec
P
P
Cancer Immunotherapy Research Laboratory, Ecole Pratique des Hautes Etudes, INSERM U517, France. lagadecp@satie.u-bourgogne.fr
Raynal
S
S
Lieubeau
B
B
Onier
N
N
Arnould
L
L
Saint-Giorgio
V
V
Lawrence
D A
DA
Jeannin
J F
JF
D030201:Activin Receptors, Type I; D000818:Animals; D002277:Carcinoma / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism*; D015536:Down-Regulation; D005260:Female; D007167:Immunotherapy; D007424:Intracellular Fluid / Q000378:metabolism*; D008050:Lipid A / Q000627:therapeutic use; D008297:Male; D009368:Neoplasm Transplantation; D009569:Nitric Oxide / Q000096:biosynthesis* / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis; D016372:RNA, Antisense / Q000235:genetics / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000096:biosynthesis; D015290:Second Messenger Systems / Q000502:physiology; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D014407:Tumor Cells, Cultured
D008050:Lipid A; D016372:RNA, Antisense; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; C000625843:Tgfbr1 protein, rat