Coordinated increase in activities of the signal transduction enzymes PI kinase and PIP kinase in human cancer cells.
The steady-state activities of the first two enzymes of the phosphatidylinositol (PI) phosphorylation pathway, PI 4-kinase, EC 2.7.1.67 (PI kinase) and PI 4-phosphate 5-kinase, EC 2.7.1.68 (PIP kinase) as compared to human normal ovary are elevated in human ovarian carcinomas (4.1- and 2.7-fold) and in human OVCAR-5 cells in tissue culture (31.2- and 8.9-fold). Compared to normal human breast parenchymal cells. PI kinase and PIP kinase activities were increased in breast carcinoma MDA-MB-435 cells grown in nude mice as solid tumors (7.3- and 2.3-fold, respectively) and in MDA-MB-435 cells grown in tissue culture (95.8- and 15.5-fold, respectively). When the human carcinoma cells were plated and expressed their neoplastic proliferative program in the log phase, in the MDA-MB-435 breast carcinoma cells the PI and PIP kinase activities coordinately increased 11-fold; in ovarian carcinoma OVCAR-5 cells 5.8- and 4.5-fold, respectively. These studies provide the first evidence in human cancer cells of an increased capacity for the operation of signal transduction. This is indicated by the markedly elevated activities of PI and PIP kinases in the phosphatidylinositol phosphorylation sequence which leads to production of second messengers, inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG).
Laboratory for Experimental Oncology, Indiana University School of Medicine, Indianapolis 46202-5200.
R L
RL
Singhal
Y A
YA
Yeh
K Y
KY
Look
G W
GW
Sledge
G
G
Weber
D019870:1-Phosphatidylinositol 4-Kinase; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001940:Breast / Q000201:enzymology / Q000502:physiology; D001943:Breast Neoplasms / Q000201:enzymology* / Q000503:physiopathology*; D002455:Cell Division / Q000502:physiology; D003864:Depression, Chemical; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D006801:Humans; D008099:Liver / Q000201:enzymology / Q000502:physiology; D008114:Liver Neoplasms, Experimental / Q000201:enzymology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008812:Mice, Hairless; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000201:enzymology* / Q000503:physiopathology*; D010053:Ovary / Q000201:enzymology / Q000502:physiology; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D011912:Rats, Inbred ACI; D012254:Ribavirin / Q000031:analogs & derivatives / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D012254:Ribavirin; D017853:Phosphotransferases (Alcohol Group Acceptor); D019870:1-Phosphatidylinositol 4-Kinase; C020077:1-phosphatidylinositol-4-phosphate 5-kinase; C033706:tiazofurin