Di Popolo A, Memoli A, Apicella A, Tuccillo C, di Palma A, Ricchi P, Acquaviva A M, Zarrilli R
Dipartimento 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, Italy.
Oncogene. 2000 Nov 16;19(48):5517-24. doi: 10.1038/sj.onc.1203952.
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.
非甾体抗炎药可降低结肠癌风险，且这种作用部分是通过抑制2型前列腺素内过氧化物合酶/环氧化酶（COX-2）介导的。在本研究中，我们证明在Caco-2结肠癌细胞中，COX-2表达和PGE2合成通过IGF-II/IGF-I受体自分泌途径上调。与汇合后分化的细胞相比，增殖细胞以及组成性过表达IGF-II的细胞中COX-2 mRNA和PGE2水平更高。IGF-II对COX-2表达的上调是通过IGF-I受体的激活介导的，因为：（i）用针对IGF-I受体的阻断抗体处理Caco-2细胞可抑制COX-2 mRNA表达；（ii）用显性负性IGF-I受体转染Caco-2细胞可降低COX-2表达和活性。此外，介导IGF-I受体在Caco-2细胞中增殖作用的PI3激酶的阻断，可抑制IGF-II依赖性COX-2上调和PGE2合成。此外，在亲本细胞、IGF-II和显性负性IGF-I受体转染细胞中，COX-2表达和活性与凋亡增加呈负相关。本研究表明，IGF-II/IGF-I受体途径诱导结肠癌细胞增殖和肿瘤进展可能依赖于COX-2相关事件的激活。
