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

Oncogene. 2002 Nov 28;21(54):8240-50. doi: 10.1038/sj.onc.1206058.

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 approximately 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD
  • Apoptosis / physiology*
  • Base Sequence
  • DNA Primers
  • Enzyme-Linked Immunosorbent Assay
  • Insulin-Like Growth Factor II / physiology*
  • Leiomyosarcoma / metabolism*
  • Leiomyosarcoma / pathology
  • Phosphorylation
  • Protein-Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • RNA, Messenger / genetics
  • Receptor, IGF Type 1 / genetics
  • Receptor, IGF Type 1 / physiology*
  • Receptor, Insulin / genetics
  • Receptor, Insulin / metabolism
  • Receptor, Insulin / physiology*
  • Signal Transduction
  • Tumor Cells, Cultured
  • Viral Proteins / metabolism

Substances

  • Antigens, CD
  • DNA Primers
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • TRS1 protein, Human herpesvirus 5
  • Viral Proteins
  • Insulin-Like Growth Factor II
  • INSR protein, human
  • Receptor, IGF Type 1
  • Receptor, Insulin
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt