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IGF-II/IGF-I receptor pathway up-regulates COX-2 mRNA expression and PGE2 synthesis in Caco-2 human colon carcinoma cells

Oncogene volume 19, pages 5517–5524 (2000)Cite this article

Abstract

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.

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Abbreviations

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

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Acknowledgements

We thank Dr D LeRoith (NIH, Bethesda, MD, USA) for kindly providing the dnIGF-Ir vector, Drs D Zanzi and G Ruggiero for help in FACS analysis, and Dr M Romano for critical reading of the manuscript. We also thank M Berardone for the artwork and R Cerillo for technical support. This work was supported by grants from Associazione Italiana per la Ricerca sul Cancro (AIRC) and Ministero dell'Università per la Ricerca Scientifica e Tecnologica (MURST). Dr A Apicella was recipient of a fellowship from Fondazione Italiana per la Ricerca sul Cancro (FIRC).

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Authors and Affiliations

  1. 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, 80131, Italy

    Anna Di Popolo, Annamaria Memoli, Anna Apicella, Concetta Tuccillo, Antonella di Palma, Paolo Ricchi, Angela M Acquaviva & Raffaele Zarrilli

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

    Concetta Tuccillo

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  1. Anna Di Popolo
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  2. Annamaria Memoli
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Di Popolo, A., Memoli, A., Apicella, A. et al. IGF-II/IGF-I receptor pathway up-regulates COX-2 mRNA expression and PGE2 synthesis in Caco-2 human colon carcinoma cells. Oncogene 19, 5517–5524 (2000). https://doi.org/10.1038/sj.onc.1203952

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