Targeting IRS-1/2 in Uveal Melanoma Inhibits In Vitro Cell Growth, Survival and Migration, and In Vivo Tumor Growth
Uveal melanoma originating in the eye and metastasizing to the liver is associated with poor prognosis and has only one approved therapeutic option. We hypothesized that liver-borne growth factors may contribute to UM growth. Therefore, we investigated the role of IGF-1/IGF-1R signaling in UM. Here,...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-12-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/24/6247 |
| _version_ | 1797461006174126080 |
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| author | Chandrani Chattopadhyay Rajat Bhattacharya Jason Roszik Fatima S. Khan Gabrielle A. Wells Hugo Villanueva Yong Qin Rishav Bhattacharya Sapna P. Patel Elizabeth A. Grimm |
| author_facet | Chandrani Chattopadhyay Rajat Bhattacharya Jason Roszik Fatima S. Khan Gabrielle A. Wells Hugo Villanueva Yong Qin Rishav Bhattacharya Sapna P. Patel Elizabeth A. Grimm |
| author_sort | Chandrani Chattopadhyay |
| collection | DOAJ |
| description | Uveal melanoma originating in the eye and metastasizing to the liver is associated with poor prognosis and has only one approved therapeutic option. We hypothesized that liver-borne growth factors may contribute to UM growth. Therefore, we investigated the role of IGF-1/IGF-1R signaling in UM. Here, we found that IRS-1, the insulin receptor substrate, is overexpressed in both UM cells and tumors. Since we previously observed that IGF-1R antibody therapy was not clinically effective in UM, we investigated the potential of NT157, a small molecule inhibitor of IRS-1/2, in blocking this pathway in UM. NT157 treatment of multiple UM cell lines resulted in reduced cell growth and migration and increased apoptosis. This treatment also significantly inhibited UM tumor growth in vivo, in the chicken egg chorioallantoic membrane (CAM) and subcutaneous mouse models, validating the in vitro effect. Mechanistically, through reverse phase protein array (RPPA), we identified significant proteomic changes in the PI3K/AKT pathway, a downstream mediator of IGF-1 signaling, with NT157 treatment. Together, these results suggest that NT157 inhibits cell growth, survival, and migration in vitro, and tumor growth in vivo via inhibiting IGF-1 signaling in UM. |
| first_indexed | 2024-03-09T17:14:15Z |
| format | Article |
| id | doaj.art-486a702b9adf40cb822bab36bfc8ddb0 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T17:14:15Z |
| publishDate | 2022-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-486a702b9adf40cb822bab36bfc8ddb02023-11-24T13:48:45ZengMDPI AGCancers2072-66942022-12-011424624710.3390/cancers14246247Targeting IRS-1/2 in Uveal Melanoma Inhibits In Vitro Cell Growth, Survival and Migration, and In Vivo Tumor GrowthChandrani Chattopadhyay0Rajat Bhattacharya1Jason Roszik2Fatima S. Khan3Gabrielle A. Wells4Hugo Villanueva5Yong Qin6Rishav Bhattacharya7Sapna P. Patel8Elizabeth A. Grimm9Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USADepartment of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USADepartment of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USADepartment of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USAPatient Derived Xenograft and Advanced In Vivo Models Core, and Department of Otolaryngology—Head and Neck Surgery, Baylor College of Medicine, Houston, TX 77030, USAPatient Derived Xenograft and Advanced In Vivo Models Core, and Department of Otolaryngology—Head and Neck Surgery, Baylor College of Medicine, Houston, TX 77030, USADepartment of Pharmaceutical Sciences, The University of Texas at El Paso, El Paso, TX 79968, USACollege of Agriculture and Life Sciences, Texas A & M at College Station, College Station, TX 77843, USADepartment of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USADepartment of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USAUveal melanoma originating in the eye and metastasizing to the liver is associated with poor prognosis and has only one approved therapeutic option. We hypothesized that liver-borne growth factors may contribute to UM growth. Therefore, we investigated the role of IGF-1/IGF-1R signaling in UM. Here, we found that IRS-1, the insulin receptor substrate, is overexpressed in both UM cells and tumors. Since we previously observed that IGF-1R antibody therapy was not clinically effective in UM, we investigated the potential of NT157, a small molecule inhibitor of IRS-1/2, in blocking this pathway in UM. NT157 treatment of multiple UM cell lines resulted in reduced cell growth and migration and increased apoptosis. This treatment also significantly inhibited UM tumor growth in vivo, in the chicken egg chorioallantoic membrane (CAM) and subcutaneous mouse models, validating the in vitro effect. Mechanistically, through reverse phase protein array (RPPA), we identified significant proteomic changes in the PI3K/AKT pathway, a downstream mediator of IGF-1 signaling, with NT157 treatment. Together, these results suggest that NT157 inhibits cell growth, survival, and migration in vitro, and tumor growth in vivo via inhibiting IGF-1 signaling in UM.https://www.mdpi.com/2072-6694/14/24/6247uveal melanoma (UM)liver metastasisinsulin-like growth factor (IGF-1) and its receptor (IGF-1R)insulin receptor substrates (IRS-1/2)NT157cell growth |
| spellingShingle | Chandrani Chattopadhyay Rajat Bhattacharya Jason Roszik Fatima S. Khan Gabrielle A. Wells Hugo Villanueva Yong Qin Rishav Bhattacharya Sapna P. Patel Elizabeth A. Grimm Targeting IRS-1/2 in Uveal Melanoma Inhibits In Vitro Cell Growth, Survival and Migration, and In Vivo Tumor Growth Cancers uveal melanoma (UM) liver metastasis insulin-like growth factor (IGF-1) and its receptor (IGF-1R) insulin receptor substrates (IRS-1/2) NT157 cell growth |
| title | Targeting IRS-1/2 in Uveal Melanoma Inhibits In Vitro Cell Growth, Survival and Migration, and In Vivo Tumor Growth |
| title_full | Targeting IRS-1/2 in Uveal Melanoma Inhibits In Vitro Cell Growth, Survival and Migration, and In Vivo Tumor Growth |
| title_fullStr | Targeting IRS-1/2 in Uveal Melanoma Inhibits In Vitro Cell Growth, Survival and Migration, and In Vivo Tumor Growth |
| title_full_unstemmed | Targeting IRS-1/2 in Uveal Melanoma Inhibits In Vitro Cell Growth, Survival and Migration, and In Vivo Tumor Growth |
| title_short | Targeting IRS-1/2 in Uveal Melanoma Inhibits In Vitro Cell Growth, Survival and Migration, and In Vivo Tumor Growth |
| title_sort | targeting irs 1 2 in uveal melanoma inhibits in vitro cell growth survival and migration and in vivo tumor growth |
| topic | uveal melanoma (UM) liver metastasis insulin-like growth factor (IGF-1) and its receptor (IGF-1R) insulin receptor substrates (IRS-1/2) NT157 cell growth |
| url | https://www.mdpi.com/2072-6694/14/24/6247 |
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