Cyclooxygenase-2 modulates the insulin-like growth factor axis in non-small-cell lung cancer.
Constitutive overexpression of cyclooxygenase-2 (COX-2) occurs frequently in several different malignancies, including lung, colon, breast, and prostate cancer. Clinical studies have established elevated serum insulin-like growth factor (IGF-I) content and IGF-I:IGF-binding protein 3 (IGFBP-3) ratio as risk factors for these same malignancies. Therefore, we sought to determine the link between COX-2 expression and the IGF axis in COX-2 gene-modified human non-small-cell lung cancer (NSCLC) cells. Overexpression of COX-2 in NSCLC cells enhanced the antiapoptotic and mitogenic effects of IGF-I and IGF-II, facilitated the autophosphorylation of the type 1 IGF receptor, increased class IA phosphatidylinositol 3'-kinase activity, and decreased expression of IGFBP-3. Thus, these findings show that COX-2 augments the stimulatory arm of the IGF axis.
Põld
Mehis
M
Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California 90095, USA.
Krysan
Kostyantyn
K
Põld
Anu
A
Dohadwala
Mariam
M
Heuze-Vourc'h
Nathalie
N
Mao
Jenny T
JT
Riedl
Karen L
KL
Sharma
Sherven
S
Dubinett
Steven M
SM
D017209:Apoptosis / Q000502:physiology; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D000068579:Celecoxib; D002455:Cell Division / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D051546:Cyclooxygenase 2; D016373:DNA, Antisense / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000096:biosynthesis; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology / Q000502:physiology*; D007335:Insulin-Like Growth Factor II / Q000494:pharmacology / Q000502:physiology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D008175:Lung Neoplasms / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D011720:Pyrazoles; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013449:Sulfonamides / Q000494:pharmacology
D000068579:Celecoxib; D051546:Cyclooxygenase 2; D016373:DNA, Antisense; D018972:Insulin-Like Growth Factor Binding Protein 3; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D007527:Isoenzymes; D008565:Membrane Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011451:Prostaglandin-Endoperoxide Synthases; D011720:Pyrazoles; D017526:Receptor, IGF Type 1; D013449:Sulfonamides; C496540:PTGS2 protein, human