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NT157 has antineoplastic effects and inhibits IRS1/2 and STAT3/5 in JAK2V617F-positive myeloproliferative neoplasm cells.

Abstract

Recent data indicate that IGF1R/IRS signaling is a potential therapeutic target in BCR-ABL1-negative myeloproliferative neoplasms (MPN); in this pathway, IRS2 is involved in the malignant transformation induced by JAK2V617F, and upregulation of IGF1R signaling induces the MPN phenotype. NT157, a synthetic compound designed as an IGF1R-IRS1/2 inhibitor, has been shown to induce antineoplastic effects in solid tumors. Herein, we aimed to characterize the molecular and cellular effects of NT157 in JAK2V617F-positive MPN cell lines (HEL and SET2) and primary patient hematopoietic cells. In JAK2V617F cell lines, NT157 decreased cell viability, clonogenicity, and cell proliferation, resulting in increases in apoptosis and cell cycle arrest in the G2/M phase (p < 0.05). NT157 treatment inhibited IRS1/2, JAK2/STAT, and NFκB signaling, and it activated the AP-1 complex, downregulated four oncogenes (CCND1, MYB, WT1, and NFKB1), and upregulated three apoptotic-related genes (CDKN1A, FOS, and JUN) (p < 0.05). NT157 induced genotoxic stress in a JAK2/STAT-independent manner. NT157 inhibited erythropoietin-independent colony formation in cells from polycythemia vera patients (p < 0.05). These findings further elucidate the mechanism of NT157 action in a MPN context and suggest that targeting IRS1/2 proteins may represent a promising therapeutic strategy for MPN.

Authors+Show Affiliations

1Department of Medical Images, Hematology, and Clinical Oncology, University of São Paulo at Ribeirão Preto Medical School, Ribeirão Preto, São Paulo Brazil. 2Center for Cell-Based Therapy, Sao Paulo Research Foundation, Ribeirão Preto, São Paulo Brazil.1Department of Medical Images, Hematology, and Clinical Oncology, University of São Paulo at Ribeirão Preto Medical School, Ribeirão Preto, São Paulo Brazil. 2Center for Cell-Based Therapy, Sao Paulo Research Foundation, Ribeirão Preto, São Paulo Brazil.1Department of Medical Images, Hematology, and Clinical Oncology, University of São Paulo at Ribeirão Preto Medical School, Ribeirão Preto, São Paulo Brazil. 2Center for Cell-Based Therapy, Sao Paulo Research Foundation, Ribeirão Preto, São Paulo Brazil.1Department of Medical Images, Hematology, and Clinical Oncology, University of São Paulo at Ribeirão Preto Medical School, Ribeirão Preto, São Paulo Brazil. 2Center for Cell-Based Therapy, Sao Paulo Research Foundation, Ribeirão Preto, São Paulo Brazil.1Department of Medical Images, Hematology, and Clinical Oncology, University of São Paulo at Ribeirão Preto Medical School, Ribeirão Preto, São Paulo Brazil. 2Center for Cell-Based Therapy, Sao Paulo Research Foundation, Ribeirão Preto, São Paulo Brazil.1Department of Medical Images, Hematology, and Clinical Oncology, University of São Paulo at Ribeirão Preto Medical School, Ribeirão Preto, São Paulo Brazil.3Knight Cancer Institute, Oregon Health & Science University, Portland, OR USA. 4Howard Hughes Medical Institute, Portland, OR USA.3Knight Cancer Institute, Oregon Health & Science University, Portland, OR USA. 4Howard Hughes Medical Institute, Portland, OR USA.3Knight Cancer Institute, Oregon Health & Science University, Portland, OR USA. 4Howard Hughes Medical Institute, Portland, OR USA.1Department of Medical Images, Hematology, and Clinical Oncology, University of São Paulo at Ribeirão Preto Medical School, Ribeirão Preto, São Paulo Brazil. 2Center for Cell-Based Therapy, Sao Paulo Research Foundation, Ribeirão Preto, São Paulo Brazil. 5Present Address: Department of Internal Medicine, University of São Paulo Medical School, São Paulo, Brazil.1Department of Medical Images, Hematology, and Clinical Oncology, University of São Paulo at Ribeirão Preto Medical School, Ribeirão Preto, São Paulo Brazil. 6Present Address: Department of Pharmacology, Institute of Biomedical Sciences of the University of São Paulo, São Paulo, Brazil.1Department of Medical Images, Hematology, and Clinical Oncology, University of São Paulo at Ribeirão Preto Medical School, Ribeirão Preto, São Paulo Brazil. 2Center for Cell-Based Therapy, Sao Paulo Research Foundation, Ribeirão Preto, São Paulo Brazil.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31993221

Citation

Fenerich, Bruna Alves, et al. "NT157 Has Antineoplastic Effects and Inhibits IRS1/2 and STAT3/5 in JAK2V617F-positive Myeloproliferative Neoplasm Cells." Signal Transduction and Targeted Therapy, vol. 5, 2020, p. 5.
Fenerich BA, Fernandes JC, Rodrigues Alves APN, et al. NT157 has antineoplastic effects and inhibits IRS1/2 and STAT3/5 in JAK2V617F-positive myeloproliferative neoplasm cells. Signal Transduct Target Ther. 2020;5:5.
Fenerich, B. A., Fernandes, J. C., Rodrigues Alves, A. P. N., Coelho-Silva, J. L., Scopim-Ribeiro, R., Scheucher, P. S., Eide, C. A., Tognon, C. E., Druker, B. J., Rego, E. M., Machado-Neto, J. A., & Traina, F. (2020). NT157 has antineoplastic effects and inhibits IRS1/2 and STAT3/5 in JAK2V617F-positive myeloproliferative neoplasm cells. Signal Transduction and Targeted Therapy, 5, 5. https://doi.org/10.1038/s41392-019-0102-5
Fenerich BA, et al. NT157 Has Antineoplastic Effects and Inhibits IRS1/2 and STAT3/5 in JAK2V617F-positive Myeloproliferative Neoplasm Cells. Signal Transduct Target Ther. 2020;5:5. PubMed PMID: 31993221.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - NT157 has antineoplastic effects and inhibits IRS1/2 and STAT3/5 in JAK2V617F-positive myeloproliferative neoplasm cells. AU - Fenerich,Bruna Alves, AU - Fernandes,Jaqueline Cristina, AU - Rodrigues Alves,Ana Paula Nunes, AU - Coelho-Silva,Juan Luiz, AU - Scopim-Ribeiro,Renata, AU - Scheucher,Priscila Santos, AU - Eide,Christopher A, AU - Tognon,Cristina E, AU - Druker,Brian J, AU - Rego,Eduardo Magalhães, AU - Machado-Neto,João Agostinho, AU - Traina,Fabiola, Y1 - 2020/01/24/ PY - 2019/03/22/received PY - 2019/11/15/revised PY - 2019/11/24/accepted PY - 2020/1/30/entrez PY - 2020/1/30/pubmed PY - 2020/1/30/medline KW - Haematological cancer KW - Preclinical research SP - 5 EP - 5 JF - Signal transduction and targeted therapy JO - Signal Transduct Target Ther VL - 5 N2 - Recent data indicate that IGF1R/IRS signaling is a potential therapeutic target in BCR-ABL1-negative myeloproliferative neoplasms (MPN); in this pathway, IRS2 is involved in the malignant transformation induced by JAK2V617F, and upregulation of IGF1R signaling induces the MPN phenotype. NT157, a synthetic compound designed as an IGF1R-IRS1/2 inhibitor, has been shown to induce antineoplastic effects in solid tumors. Herein, we aimed to characterize the molecular and cellular effects of NT157 in JAK2V617F-positive MPN cell lines (HEL and SET2) and primary patient hematopoietic cells. In JAK2V617F cell lines, NT157 decreased cell viability, clonogenicity, and cell proliferation, resulting in increases in apoptosis and cell cycle arrest in the G2/M phase (p < 0.05). NT157 treatment inhibited IRS1/2, JAK2/STAT, and NFκB signaling, and it activated the AP-1 complex, downregulated four oncogenes (CCND1, MYB, WT1, and NFKB1), and upregulated three apoptotic-related genes (CDKN1A, FOS, and JUN) (p < 0.05). NT157 induced genotoxic stress in a JAK2/STAT-independent manner. NT157 inhibited erythropoietin-independent colony formation in cells from polycythemia vera patients (p < 0.05). These findings further elucidate the mechanism of NT157 action in a MPN context and suggest that targeting IRS1/2 proteins may represent a promising therapeutic strategy for MPN. SN - 2059-3635 UR - https://www.unboundmedicine.com/medline/citation/31993221/NT157_has_antineoplastic_effects_and_inhibits_IRS1/2_and_STAT3/5_in_JAK2V617F_positive_myeloproliferative_neoplasm_cells_ L2 - https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/31993221/ DB - PRIME DP - Unbound Medicine ER -