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In IGF-I receptor-deficient leiomyosarcoma cells autocrine IGF-II induces cell invasion and protection from apoptosis via the insulin receptor isoform A

Oncogene volume 21, pages 8240–8250 (2002)Cite this article

Abstract

One of the two isoforms of the human insulin receptor (isoform A or IR-A) binds IGF-II with high affinity and is predominantly expressed in fetal tissues and malignant cells. We evaluated the biological relevance of IR-A in human myosarcoma cells. Six myosarcoma cell lines were studied. All produced high amounts of IGF-II and five of them predominantly expressed IR-A. SKUT-1 leiomyosarcoma cells, that do not express the IGF-IR, were identified as a suitable model to study the effects of IR-A in the absence of the interference of IGF-IR. In these cells, which express high levels of IR with an IR-A relative abundance of ≈95%, IGF-II elicits biological effects exclusively via IR-A activation and IGF-I is almost ineffective. Blockade of autocrine IGF-II reduced unstimulated cell viability and migration. Although both insulin and IGF-II activate IR-A, these two ligands showed a different ability to activate different intracellular signaling pathways and to elicit different biological effects. Insulin was more potent than IGF-II in activating the PI3-K/Akt pathway and in protecting cells from apoptosis. In contrast, IGF-II was more potent than insulin in activating the Shc/ERK pathway and in stimulating cell migration. These data indicate that IGF-II sensitive IR-A is the predominant IR isoform in a variety of myosarcoma cells. In SKUT-1 leiomyoma cells this fetal IR isoform may vicariate the IGF-IR for cell response to both insulin and IGF-II. Acting on the same IR-A receptor IGF-II is more potent than insulin in stimulating cancer cell migration.

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Acknowledgements

We thank Dr A Colombatti, Aviano, Italy, and Dr P Russo, Catania, Italy, for kindly providing us with the sarcoma cells. This work was supported in part by grants from the Associazione Italiana per la Ricerca sul Cancro (AIRC), MURST (Cofin 2001 to A Belfiore) and MURST (cod. 202, 1998–2000 to R Vigneri).

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Authors and Affiliations

  1. Dipartimento di Medicina Interna e Medicina Specialistica, University of Catania, Ospedale Garibaldi, Catania, 95123, Italy

    Laura Sciacca, Rossana Mineo, Giuseppe Pandini & Riccardo Vigneri

  2. I.M.O., Istituto Mediterraneo di Oncologia, Catania, Italy

    Giuseppe Pandini & Riccardo Vigneri

  3. Dipartimento di Medicina Clinica e Sperimentale, Cattedra di Endocrinologia, University of Catanzaro, Policlinico Mater Domini, via T. Campanella 115, Catanzaro, 88100, Italy

    Antonella Murabito & Antonino Belfiore

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  1. Laura Sciacca
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  2. Rossana Mineo
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Correspondence to Antonino Belfiore.

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Sciacca, L., Mineo, R., Pandini, G. et al. In IGF-I receptor-deficient leiomyosarcoma cells autocrine IGF-II induces cell invasion and protection from apoptosis via the insulin receptor isoform A. Oncogene 21, 8240–8250 (2002). https://doi.org/10.1038/sj.onc.1206058

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