Inhibition of human pancreatic cancer cell (MIA PaCa-2) growth by cholera toxin and 8-chloro-cAMP in vitro

• Published in: British journal of cancer Vol. 67; no. 2; pp. 279 - 283
• Main Authors: OHMURA, E, WAKAI, K, ISOZAKI, O, MURAKAMI, H, ONODA, N, EMOTO, N, SHIZUME, K, TSUSHIMA, T, DEMURA, H, ROBINS, R. K
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01.02.1993
• Subjects: 8-Bromo Cyclic Adenosine Monophosphate - analogs & derivatives; 8-Bromo Cyclic Adenosine Monophosphate - pharmacology; Antineoplastic agents; Antineoplastic Agents - pharmacology; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Biological and medical sciences; Cell Division - drug effects; Cholera Toxin - pharmacology; Colforsin - pharmacology; Cyclic AMP - biosynthesis; Drug Synergism; Epidermal Growth Factor - metabolism; General aspects; Humans; Immunologic Factors - pharmacology; Insulin-Like Growth Factor I - metabolism; Medical sciences; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Pharmacology. Drug treatments; Proto-Oncogene Proteins p21(ras) - metabolism; Tetradecanoylphorbol Acetate - pharmacology; Tumor Cells, Cultured - drug effects; Human; Antineoplastic agent; Carcinoma; Cytostatic; Cyclic AMP; Malignant tumor; In vitro; Infection; Toxin; Analog; Established cell line; Bacteriosis; Digestive diseases; Cholera; Mechanism of action; Pancreas; Pancreatic disease
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.1993.53

The effects of cholera toxin (CT) and 8-chloro-cAMP (8-Cl-cAMP) on cell growth were investigated using two human pancreatic carcinoma cell lines (MIA PaCa-2, Panc-1). CT, which catalyses the ADP ribosylation of Gs, suppresses the proliferation of MIA PaCa-2(PC) cells. CT at the low dose of 0.1 pg ml-1 was inhibitory of PC cell growth, and the maximum suppression (70%) was achieved at a CT concentration of 100 pg ml-1. This phenomenon was reversible. The production of cAMP by CT (100 pg ml-1) in PC cells was enhanced 320-fold compared with the control. In addition, cAMP analogues (8-Cl-cAMP, 8-Br-cAMP) and forskolin decreased the growth rate of PC cells in a dose-dependent manner. These results support the view that CT suppresses PC cell growth by stimulating cAMP production. Conversely, Panc-1 cells were far less sensitive to CT in cell growth and cAMP production. 8-Cl-cAMP was also less effective on Panc-1 cell growth. The binding of an insulin-like growth factor (IGF)-I and transforming growth factor (TGF)-alpha, which has been shown to stimulate PC cell growth in an autocrine manner, to PC cells was not modified in cells treated with CT or 8-Cl-cAMP. The results suggest that the inhibitory actions of these substances do not occur at the level of the receptor for IGF-I or EGF/TGF-alpha. We have previously shown that phorbol esters, which decrease the binding of TGF-alpha to PC cells, has an anti-proliferative activity on these tumour cells. Inhibited cell growth by maximum suppressive dose of CT or 8-Cl-cAMP was further inhibited by TPA. In addition, an oncogene product of K-ras which is commonly activated in pancreatic cancer, was increased by CT and 8-Cl-cAMP. It is concluded that CT and 8-Cl-cAMP inhibit PC cell growth, presumably in a similar manner, and their mechanism(s) of action may be different from that of TPA. The anti-proliferative effect of CT or 8-Cl-cAMP was enhanced by TPA, implying that the combination of these substances results in increased inhibition of the PC cell growth.