Insulin-like growth factor 1 receptor, novel functions and future possibilities

Insulin like growth factor-1 receptor (IGF-1R) has been shown to be important for cancer cell growth and survival, and is often overexpressed in malignant and premalignant tissues. Ligand binding to IGF-1R induces transphosphorylation and activation of the receptor, leading to subsequent activation of the phosphatidyl inositol-3 kinase (PI3K), the mitogen-activated protein kinase (MAPK) and the 14-3-3 pathways. Most of these pathways are shared by other receptor tyrosine kinases. Inhibition of these pathways using specific IGF-1R antibodies has, however, failed in large trials on cancer patients. This opens the possibilities for alternative signaling pathways. Recently, IGF-1R was shown to be SUMOylated and translocated to the cell nucleus. In the nucleus it binds to enhancer-like regions, and regulates expression of genes including CCND1 and AXIN2, and phosphorylates Histone3. The expression of nuclear IGF-1R has also been linked to increased cell growth and aggressive phenotype in cancer.

In paper I the effects of picropodophyllin (PPP), an inhibitor of IGF-1R, on cell cycle progression were studied. Previous studies have indicated that PPP treated cells arrest in G2/M. We found that PPP induced G2/M arrest through interfering with microtubule dynamics causing prolonged mitotic arrest and mitotic catastrophe in an IGF-1R independent manner. This mechanism of PPP may contribute to its efficacy in treatment of cancer patients. In paper II the roles of SUMOylated IGF-1R in regulating cell proliferation and cell cycle progression were investigated. We provided evidence that SUMOylation of IGF-1R increases G1/S phase transition through inducing expression of cyclins (D, A and B) and upregulating CDK2. Cells expressing SUMOylated IGF-1R also proliferated faster and formed more colonies in soft agar compared to cells expressing IGF1R with mutated SUMO-binding sites. In paper III we investigated potential binding partners to nuclear IGF-1R in human embryonic stem cells (hESC). We found that nuclear IGF-1R associates with PCNA and phosphorylates it, not only in hESCs but also in other cell types. The nuclear IGF-1R-induced PCNA phosphorylation was followed by ubiquitination of PCNA, probably through DNA damage tolerance (DDT)-dependent E2/E3 ligases (e.g. Rad18 and UBC13). Our data suggest that IGF-1R may contribute to activation of DDT, as externally induced DNA damage in IGF-1R negative cells led to G1 cell cycle arrest and larger S-phase fork stalling compared to cells expressing IGF-1R.

In summary, the achieved results may contribute in understanding the complexity of IGF-1R’s roles in cell growth and maintenance of genome stability, as well as the shown mitotic block induced by PPP may be a mechanism that favors anti-IGF-1R treatment in cancer.

List of scientific papers

I. Waraky, A., Akopyan, K., Parrow, V., Stromberg, T., Axelson, M., Abrahmsen, L., Lindqvist, A., Larsson, O., and Aleem, E. (2014). Picropodophyllin causes mitotic arrest and catastrophe by depolymerizing microtubules via insulin-like growth factor-1 receptor-independent mechanism. Oncotarget. 5, 8379-8392.
https://doi.org/10.18632/oncotarget.2292

II. Lin, Y., Liu, H., Waraky, A., Haglund, F., Agarwal, P., Jernberg-Wiklund, H., Warsito, D., Larsson, O. (2017). SUMO-modified insulin-like growth factor 1 receptor (IGF-1R) increases cell cycle progression and cell proliferation. Journal of Cellular Physiology. 232, 2722-2730.
https://doi.org/10.1002/jcp.25818

III. Waraky, A., Lin, Y., Warsito, D., Haglund, F., Aleem, E., Larsson, O. (2017). Nuclear insulin-like growth factor 1 receptor phosphorylates proliferating cell nuclear antigen and rescues stalled replication forks after DNA damage. [Submitted]