Abstract
The insulin-like growth factor 1 receptor (IGF1R) is a receptor-type tyrosine kinase that transduces signals related to cell proliferation, differentiation, and survival. IGF1R expression is often misregulated in tumor cells, but the relevance of this for cancer progression remains unclear. Here, we examined the impact of IGF1R inhibition on cell division. We found that siRNA-mediated knockdown of IGF1R from HeLa S3 cells leads to M-phase delays. Although IGF1R depletion causes partial exclusion of FoxM1 from the nucleus, quantitative real-time PCR revealed that the transcription of M-phase regulators is not affected by decreased levels of IGF1R. Moreover, a similar delay in M phase was observed following 2 h of incubation with the IGF1R inhibitors OSI-906 and NVP-ADW742. These results suggest that the M-phase delay observed in IGF1R-compromised cells is not caused by altered expression of mitotic regulators. Live-cell imaging revealed that both prolonged prometaphase and prolonged metaphase underlie the delay and this can be abrogated by the inhibition of Mps1 with AZ3146, suggesting activation of the Spindle Assembly Checkpoint when IGF1R is inhibited. Furthermore, incubation with the Aurora B inhibitor ZM447439 potentiated the IGF1R inhibitor-induced suppression of cell proliferation, opening up new possibilities for more effective cancer chemotherapy.
Highlights
The insulin-like growth factor 1 (IGF1) receptor is a receptor-type tyrosine kinase composed of two α and two β subunits, which are generated by cleavage of the IGF1 receptor (IGF1R) precursors [1]
The mitotic index, the ratio of the number of M-phase cells to total cell number, was not affected by IGF1R knockdown (Figure 1E). These results suggest that IGF1R plays a role in M-phase progression but not in a mitotic entry
We found that the IGF1/IGF1R signal plays a role in M-phase progression
Summary
The insulin-like growth factor 1 (IGF1) receptor is a receptor-type tyrosine kinase composed of two α and two β subunits, which are generated by cleavage of the IGF1 receptor (IGF1R) precursors [1]. Associations between increases in plasma IGF levels and cancer risk have been suggested [2,3,4,5]. The correlation of IGF1R expression levels with the progression of cancer and metastatic phenotypes has been reported [6,7,8,9,10]. Several reports have shown an inverse or no correlation between IGF1R expression levels and malignancy and survival rates [5,11,12,13,14]. Further understanding of IGF1/IGF1R signaling is required to elucidate the significance of IGF1R expression levels in cancer development and malignancy
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