Modification of IGF1R Expression on Malignant Lymphoid Cells by a Proteasome Inhibitor

Purpose: The type 1 IGF receptor (IGF1R) is a transmembrane tyrosine kinase, which is overexpressed by tumors, and mediates proliferation and apoptosis protection for tumor cells. IGF signaling affects hypoxia signaling, protease secretion, tumor cell motility, and adhesion. ProIGF1R is cleaved into alpha and beta chains by processing, and their heterodyne moves onto plasma membrane. Folding after transfer to Golgi apparatus modifies the beta chain, and it is also known to degradate by ubiquitin-proteasome system. Bortezomib is a proteasome inhibitor for multiple myeloma, and expression of chaperon proteins such as IGF1R could be increased by bortezomib. Here, we examined and analyzed expression of IGF1R on malignant lymphoid cells, and discuss possibility of IGF1R as a target in the treatment of lymphoid malignancies.

Methods: IGF1R expression of malignant T cell lymphoid cell line Jurkat, myeloma cell line IM-9, and bortezomibresistant IM-9 was examined by flow cytometric and western blot analyses. The cell lines were cultured with IGF1 and IGF2 with or without bortezomib, and the growth and cell death were observed.

Results: The IGF1R expression on Jurkat cells was weak by flow cytometry, and western blot analysis revealed that IGF1R beta expression was quite low in spite of higher expression of ProIGF1R and IGF1R alpha. The IGF1R expression on bortezomib-resistant cells was stronger than that on parent IM-9 cells by flow cytometric and western blot analyses. While IGF1 and IGF2 did not give an advantage for the growth of lymphoid cells significantly without bortezomib, there was an advantage for survival of them under exposure to bortezomib.

Conclusion: Difference of IGF1R expression was observed among several malignant lymphoid cells. Cell surface modification by drugs such as bortezomib will make lymphoid cells increased IGF1R expression, and IGF1R inhibition will be a promising way for the treatment of malignant lymphoid cells.