Effects of genetic blockade of the insulin-like growth factor receptor in human colon cancer cell lines

Gastroenterology. 2002 Oct;123(4):1191-204. doi: 10.1053/gast.2002.36023.

Abstract

Background & aims: Insulin-like growth factor (IGF)-I receptor (IGF-Ir) signaling is required for maintenance of growth and tumorigenicity of several tumor types. We have previously shown successful therapy in a lung cancer xenograft model using an adenovirus expressing antisense IGF-Ir. In this study, we sought to better dissect the mechanism and develop potentially more effective IGF-Ir-targeted therapeutics by developing and testing tetracycline-regulated and recombinant adenoviruses expressing dominant negative receptors.

Methods: Truncated IGF-I receptors (IGF-Ir/tf; 482 and 950 amino acids long, respectively [IGF-Ir/482st and IGF-Ir/950st]) were cloned into tetracycline-regulated vectors and recombinant adenoviruses and then studied in colorectal cancer cells. We assessed the effect of IGF-Ir/tf on signaling blockade, colony formation, stress response (serum starvation and heat), chemotherapy-induced apoptosis, and in vivo therapeutic efficacy in xenografts.

Results: Activation of IGF-Ir/tf expression by withdrawal of tetracycline suppressed tumorigenicity both in vitro and in vivo and up-regulated stressor-induced apoptosis. It effectively blocked both IGF-I- and IGF-II-induced activation of Akt-1. IGF-Ir/tf expression increased chemotherapy-induced apoptosis, and this combination therapy was very effective against tumors in mice. These findings were confirmed in a therapy model against established tumors using adenoviruses expressing IGF-Ir/tf. Moreover, IGF-Ir/482st was more effective than IGF-Ir/950st because of its bystander effect.

Conclusions: Anti-tumor activity of IGF-Ir/tf is mediated through inhibition of Akt-1 and enhances the efficacy of chemotherapy. Adenovirus IGF-Ir/482st may be a useful anticancer therapeutic for colorectal carcinoma.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenoviridae / genetics
  • Animals
  • Anti-Bacterial Agents / pharmacology
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Apoptosis / physiology
  • Blood Proteins / pharmacology
  • Carcinogenicity Tests
  • Cell Division / drug effects
  • Colonic Neoplasms / genetics*
  • Colonic Neoplasms / physiopathology*
  • Colonic Neoplasms / therapy
  • DNA, Complementary
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Genetic Therapy
  • HT29 Cells
  • Heat-Shock Response / physiology
  • Humans
  • Mice
  • Mice, Nude
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins*
  • Receptor, IGF Type 1 / genetics*
  • Signal Transduction / physiology
  • Tetracycline / pharmacology
  • Transfection

Substances

  • Anti-Bacterial Agents
  • Antineoplastic Agents
  • Blood Proteins
  • DNA, Complementary
  • Proto-Oncogene Proteins
  • Receptor, IGF Type 1
  • AKT1 protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Tetracycline