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The insulin receptor negatively regulates the action of Pseudomonas toxin-based immunotoxins and native Pseudomonas

Xiu Fen Liu1, David J FitzGerald, Ira Pastan

  • 1Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.

Cancer Research
|January 26, 2013
PubMed

Insights

Lowering insulin receptor levels boosts the effectiveness of SS1P immunotoxin against cancers like mesothelioma. This occurs because reduced insulin receptor levels enhance SS1P

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • SS1P is an antimesothelin immunotoxin targeting mesothelin-expressing tumors.
  • Mesothelin is found in mesothelioma, ovarian, lung, and pancreatic cancers.
  • Insulin receptor signaling is a known survival factor for cancer cells.

Purpose of the Study:

  • To investigate the effect of reducing insulin receptor levels on SS1P immunotoxin efficacy.
  • To determine the mechanism by which insulin receptor levels influence SS1P's cytotoxic action.

Main Methods:

  • Utilized siRNA to knock down insulin receptor expression in human cancer cell lines.
  • Assessed the cytotoxicity of SS1P and other agents (Pseudomonas exotoxin A, TRAIL, etoposide, cycloheximide) after insulin receptor knockdown.
  • Analyzed SS1P cleavage by furin and its subsequent effect on elongation factor 2.

Main Results:

  • siRNA-mediated insulin receptor knockdown significantly enhanced SS1P toxicity in multiple cell lines.
  • Knockdown also increased the cytotoxicity of native Pseudomonas exotoxin A.
  • The enhancement was specific to SS1P and Pseudomonas exotoxin A, not affecting responses to TRAIL, etoposide, or cycloheximide.
  • Insulin receptor knockdown increased SS1P cleavage by furin, leading to greater elongation factor 2 inactivation.

Conclusions:

  • The insulin receptor negatively regulates the cytotoxic action of SS1P immunotoxin.
  • Targeting the insulin receptor may represent a strategy to improve SS1P efficacy in treating mesothelin-expressing cancers.

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