Inhibition of the Na+,K(+)-ATPase pump during induction of experimental colon cancer.
During the development of large bowel cancer alterations in colonic epithelial ion transport have been observed some of which result in altered intracellular ionic composition. In many tumors intracellular sodium and potassium become elevated and depressed, respectively. This observation suggests that mechanisms governing intracellular homeostasis for sodium and potassium are no longer tightly regulated. Changes in cell membrane permeability, sodium, potassium-ATPase K(+)-ATPase) pump activity, or both may be responsible for these alterations. It is not known when during initiation and development of cancer such changes may occur. To assess whether there are changes in the Na+, K(+)-ATPase pump early during the induction of large bowel cancer and prior to any notable histological changes, we measured the kinetics of the Na+, K(+)-pump in distal colonic mucosa of CF1 mice one week following only four weekly injections of the carcinogen 1,2-dimethyhydrazine (DMH). The kinetics of the pump were found to be best described by a model of highly cooperative binding. The VMAX of the pump in premalignant mucosa was lower for both sodium and potassium substrate activation (55-65% of control) with little change in other kinetic parameters. Depression of VMAX could not be attributed to an increased barium blockable potassium conductance of the basolateral membrane. Na+,K(+)-ATPase activity was also decreased by 50% in the distal colon of DMH treated mice, but was not affected in the less cancer susceptible proximal colon. These data demonstrate that alterations occur in the Na+,K(+)-pump in premalignant mucosa months before gross tumors develop, and these changes may partially explain the altered levels of Na+ and K+ in the cytoplasm of pre-malignant and malignant colonocytes.
Davies
R J
RJ
Department of Surgery/Oncology, UCSD-VA Medical Center, La Jolla 92161.
Sandle
G I
GI
Thompson
S M
SM
D019813:1,2-Dimethylhydrazine; D000818:Animals; D001464:Barium / Q000494:pharmacology; D002273:Carcinogens; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000209:etiology; D004127:Dimethylhydrazines; D005260:Female; D007700:Kinetics; D051379:Mice; D008954:Models, Biological; D010042:Ouabain / Q000494:pharmacology; D011230:Precancerous Conditions / Q000201:enzymology* / Q000209:etiology; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors* / Q000187:drug effects
D002273:Carcinogens; D004127:Dimethylhydrazines; D001464:Barium; D010042:Ouabain; D000254:Sodium-Potassium-Exchanging ATPase; D019813:1,2-Dimethylhydrazine