Insulin-like growth factor 1 receptor, novel functions and future possibilities
Author: Waraky, Ahmed
Date: 2017-09-22
Location: Lecture Hall R8:00, Cancer centrum Karolinska, R8, Karolinska University hospital, Solna
Time: 09.00
Department: Inst för onkologi-patologi / Dept of Oncology-Pathology
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Abstract
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.
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 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.
Fulltext (DOI)
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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.
Fulltext (DOI)
Pubmed
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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]
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.
Fulltext (DOI)
Pubmed
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.
Fulltext (DOI)
Pubmed
View record in Web of Science®
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]
Institution: Karolinska Institutet
Supervisor: Larsson, Olle
Co-supervisor: Aleem, Eiman
Issue date: 2017-09-01
Rights:
Publication year: 2017
ISBN: 978-91-7676-789-4
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