¹Dipartimento di Biologia e Patologia Cellulare e Molecolare 'L Califano', Centro di Endocrinologia ed Oncologia Sperimentale 'G. Salvatore' del Consiglio Nazionale delle Ricerche, Università 'Federico II', Napoli, 80131 Italy

²Dipartimento di Internistica Clinica e Sperimentale-Divisione di Gastroenterologia, II Ateneo di Napoli, Napoli, 80131 Italy

Correspondence to: A M Acquaviva, Dipartimento di Biologia e Patologia Cellulare e Molecolare 'L Califano', Università 'Federico II', Via S. Pansini 5, Napoli, 80131 Italy

Nonsteroidal anti-inflammatory drugs reduce the risk of colon cancer and this effect is mediated in part through inhibition of type 2 prostaglandin endoperoxide synthase/cyclo-oxygenase (COX-2). In the present study, we demonstrate that COX-2 expression and PGE₂ synthesis are up-regulated by an IGF-II/IGF-I receptor autocrine pathway in Caco-2 colon carcinoma cells. COX-2 mRNA and PGE₂ levels are higher in proliferating cells compared with post-confluent differentiated cells and in cells that constitutively overexpress IGF-II. Up-regulation of COX-2 expression by IGF-II is mediated through activation of IGF-I receptor because: (i) treatment of Caco-2 cells with a blocking antibody to the IGF-I receptor inhibits COX-2 mRNA expression; (ii) transfection of Caco-2 cells with a dominant negative IGF-I receptor reduces COX-2 expression and activity. Also, the blockade of the PI3-kinase, that mediates the proliferative effect of IGF-I receptor in Caco-2 cells, inhibits IGF-II-dependent COX-2 up-regulation and PGE₂ synthesis. Moreover, COX-2 expression and activity inversely correlate with the increase of apoptosis in parental, IGF-II and dominant-negative IGF-I receptor transfected cells. This study suggests that induction of proliferation and tumor progression of colon cancer cells by the IGF-II/IGF-I receptor pathway may depend on the activation of COX-2-related events. Oncogene (2000) 19, 5517-5524.

IGF-II; IGF-Ir; COX-2; PGE₂; colon cancer

IGF-II, insulin-like growth factor-II; IGF-Ir, IGF-I receptor; dnIGF-Ir, dominant negative IGF-I receptor; COX, cyclo-oxygenase; PG, prostaglandin; NSAIDs, nonsteroidal anti-inflammatory drugs; RT-PCR, reverse transcription polymerase chain reaction; MAPK-kinase, mitogen-activated protein kinase-kinase; PI3-kinase, phosphatidylinositol 3-kinase