Inhibition of cancer cell proliferation and metastasis by insulin receptor downregulation

Abstract

Insulin receptor (IR) and the type I IGF receptor (IGF1R) are structurally and functionally related. The function of IGF1R in cancer has been well documented and anti-IGF1R strategies to treat cancer have shown initial positive results. However, the role of IR in tumor biology, independent of IGF1R, is less clear. To address this issue, short hairpin RNA (shRNA) was used to specifically downregulate IR in two cancer cell lines, LCC6 and T47D. Cells with reduced IR demonstrated reduced insulin-stimulated Akt activation, without affecting IGF1R activation. Cells with reduced IR formed fewer colonies in anchorage independent conditions. LCC6 IR shRNA xenograft tumors in mice had reduced growth, angiogenesis, and lymphangiogensis compared with LCC6 wild type cells. Accordingly, LCC6 IR shRNA clones produced less HIF1α, VEGF-A, and VEGF-D. Furthermore, LCC6 IR shRNA cells formed fewer pulmonary metastases compared to LCC6 wild type cells. By in vivo luciferase imaging, we have shown that LCC6 IR shRNA cells have less seeding and colonization potential in the lung and liver of mice than LCC6 cells. In conclusion, downregulation of IR inhibited cancer cell proliferation, angiogenesis, lymphangiogenesis, and metastasis. Our data argue that IR should also be targeted in cancer therapy.