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Inhibition of cancer cell proliferation and metastasis by insulin receptor downregulation

H Zhang1, D H Fagan, X Zeng

  • 1Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.

Oncogene
|February 16, 2010
PubMed

Insights

Targeting the insulin receptor (IR) inhibits cancer growth and metastasis. Downregulating IR reduces tumor proliferation, angiogenesis, and the spread of cancer cells, suggesting IR as a potential therapeutic target in oncology.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • The insulin receptor (IR) and type I IGF receptor (IGF1R) are structurally and functionally related, with IGF1R's role in cancer well-established.
  • The specific role of IR in tumor biology, independent of IGF1R, remains less understood.
  • Targeting IGF1R has shown initial promise in cancer therapy.

Purpose of the Study:

  • To investigate the independent role of the insulin receptor (IR) in cancer progression.
  • To determine if downregulating IR affects cancer cell proliferation, angiogenesis, lymphangiogenesis, and metastasis.
  • To evaluate IR as a potential therapeutic target in cancer treatment.

Main Methods:

  • Utilized short hairpin RNA (shRNA) to specifically downregulate IR in LCC6 and T47D cancer cell lines.
  • Assessed insulin-stimulated Akt activation and IGF1R activation in cells with reduced IR.
  • Evaluated colony formation in anchorage-independent conditions and xenograft tumor growth in mice.
  • Measured angiogenesis, lymphangiogenesis, and the expression of hypoxia-inducible factor-1alpha and VEGF-A/D.
  • Assessed pulmonary metastasis and in vivo seeding/colonization potential using luciferase imaging.

Main Results:

  • Downregulation of IR reduced insulin-stimulated Akt activation without affecting IGF1R activation.
  • IR-reduced cells exhibited fewer colonies in anchorage-independent assays.
  • LCC6 IR shRNA xenografts showed reduced growth, angiogenesis, and lymphangiogenesis compared to wild-type.
  • Expression of HIF-1alpha, VEGF-A, and VEGF-D was decreased in LCC6 IR shRNA clones.
  • LCC6 IR shRNA cells formed fewer pulmonary metastases and had reduced seeding/colonization potential in mice.

Conclusions:

  • Downregulation of the insulin receptor (IR) significantly inhibits cancer cell proliferation, angiogenesis, lymphangiogenesis, and metastasis.
  • IR plays a crucial role in cancer progression independent of IGF1R.
  • The findings support targeting IR as a potential therapeutic strategy in cancer therapy.

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