Gelsolin suppresses tumorigenicity through inhibiting PKC activation in a human lung cancer cell line, PC10.
Gelsolin expression is frequently downregulated in lung cancer and several types of different human cancers. To examine the effects of gelsolin restoration on tumorigenicity, we here stably expressed various levels of gelsolin via gene transfer in lung cancer cells (squamous cell carcinoma line, PC10). We observed the alterations in tumorigenicity in vivo when implanted in nude mice, and the changes in growth properties in vitro. As compared to parental cells and control clones, gelsolin transfectants highly reduced tumorigenicity and repressed cell proliferation. Moreover, we investigated bradykinin-induced responses in gelsolin-overexpressing clones, because agonist-stimulated activation of the phospholipases C (PLC)/protein kinase C (PKC) signal transduction pathway is critical for cell growth and tumorigenicity. Bradykinin promotes phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis by PLC and translocation of various PKC isoforms from the cytosolic fraction to the particulate fraction. Bradykinin treatment did not increase inositoltriphosphate (IP3) production and induce the membrane fractions of PKC alpha and PKC gamma in gelsolin tranfectants, while it induced PIP2 hydrolysis and increased the fractions in parental and control clones. These results suggest that gelsolin suppressed the activation of PKCs involved in phospholipid signalling pathways, inhibiting cell proliferation and tumorigenicity.
Sagawa
N
N
Division of Cancer Gene Regulation, Research Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
Fujita
H
H
Banno
Y
Y
Nozawa
Y
Y
Katoh
H
H
Kuzumaki
N
N
D000818:Animals; D017209:Apoptosis; D001920:Bradykinin / Q000494:pharmacology; D002455:Cell Division; D004789:Enzyme Activation; D018260:Gelsolin / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D009368:Neoplasm Transplantation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured
D018260:Gelsolin; D007527:Isoenzymes; D015544:Inositol 1,4,5-Trisphosphate; D011493:Protein Kinase C; D001920:Bradykinin