IGF1R/IRS1 targeting has cytotoxic activity and inhibits PI3K/AKT/mTOR and MAPK signaling in acute lymphoblastic leukemia cells

Ana Paula Nunes Rodrigues Alves; Jaqueline Cristina Fernandes; Bruna Alves Fenerich; Juan Luiz Coelho-Silva; Priscila Santos Scheucher; Belinda Pinto Simões; Eduardo Magalhães Rego; Anne J. Ridley; João Agostinho Machado-Neto; Fabiola Traina

doi:10.1016/j.canlet.2019.04.030

IGF1R/IRS1 targeting has cytotoxic activity and inhibits PI3K/AKT/mTOR and MAPK signaling in acute lymphoblastic leukemia cells

Ana Paula Nunes Rodrigues Alves, Jaqueline Cristina Fernandes, Bruna Alves Fenerich, Juan Luiz Coelho-Silva, Priscila Santos Scheucher, Belinda Pinto Simões, Eduardo Magalhães Rego, Anne J. Ridley, João Agostinho Machado-Neto, Fabiola Traina^*

^*Corresponding author for this work

Randall Centre of Cell & Molecular Biophysics

Research output: Contribution to journal › Article › peer-review

30 Citations (Scopus)

Abstract

The IGF1R/IRS1 signaling is activated in acute lymphoblastic leukemia (ALL)and can be targeted by the pharmacological inhibitors NT157 (IGF1R-IRS1/2 inhibitor)and OSI-906 (IGF1R/IR inhibitor). Here we investigate the cellular and molecular effects of NT157 and OSI-906 in ALL cells. NT157 and OSI-906 treatment reduced viability, proliferation and cell cycle progression in ALL cell lines. Similarly, in primary samples of patients with ALL, both OSI-906 and NT157 reduced viability, but only NT157 induced apoptosis. NT157 and OSI-906 did not show cytotoxicity in primary samples from healthy donor. NT157 and OSI-906 significantly decreased Jurkat cell migration, but did not modulate Namalwa migration. Consistent with the more potent effect of NT157 on cells, NT157 significantly modulated expression of 25 genes related to the MAPK signaling pathway in Jurkat cells, including oncogenes and tumor suppressor genes. Both compounds inhibited mTOR and p70S6K activity, but only NT157 inhibited AKT and 4-EBP1 activation. In summary, in ALL cells, NT157 has cytotoxic activity, whereas OSI-906 is cytostatic. NT157 has a stronger effect on ALL cells, and thus the direct inhibition of IRS1 may be a potential therapeutic target in ALL.

Original language	English
Pages (from-to)	59-68
Number of pages	10
Journal	Cancer Letters
Volume	456
Early online date	28 Apr 2019
DOIs	https://doi.org/10.1016/j.canlet.2019.04.030
Publication status	Published - 1 Aug 2019

Keywords

Acute lymphoblastic leukemia
Cell signaling
IGF1R/IRS1
NT157

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10.1016/j.canlet.2019.04.030

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Rodrigues Alves, A. P. N., Fernandes, J. C., Fenerich, B. A., Coelho-Silva, J. L., Scheucher, P. S., Simões, B. P., Rego, E. M., Ridley, A. J., Machado-Neto, J. A., & Traina, F. (2019). IGF1R/IRS1 targeting has cytotoxic activity and inhibits PI3K/AKT/mTOR and MAPK signaling in acute lymphoblastic leukemia cells. Cancer Letters, 456, 59-68. https://doi.org/10.1016/j.canlet.2019.04.030

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title = "IGF1R/IRS1 targeting has cytotoxic activity and inhibits PI3K/AKT/mTOR and MAPK signaling in acute lymphoblastic leukemia cells",

abstract = "The IGF1R/IRS1 signaling is activated in acute lymphoblastic leukemia (ALL)and can be targeted by the pharmacological inhibitors NT157 (IGF1R-IRS1/2 inhibitor)and OSI-906 (IGF1R/IR inhibitor). Here we investigate the cellular and molecular effects of NT157 and OSI-906 in ALL cells. NT157 and OSI-906 treatment reduced viability, proliferation and cell cycle progression in ALL cell lines. Similarly, in primary samples of patients with ALL, both OSI-906 and NT157 reduced viability, but only NT157 induced apoptosis. NT157 and OSI-906 did not show cytotoxicity in primary samples from healthy donor. NT157 and OSI-906 significantly decreased Jurkat cell migration, but did not modulate Namalwa migration. Consistent with the more potent effect of NT157 on cells, NT157 significantly modulated expression of 25 genes related to the MAPK signaling pathway in Jurkat cells, including oncogenes and tumor suppressor genes. Both compounds inhibited mTOR and p70S6K activity, but only NT157 inhibited AKT and 4-EBP1 activation. In summary, in ALL cells, NT157 has cytotoxic activity, whereas OSI-906 is cytostatic. NT157 has a stronger effect on ALL cells, and thus the direct inhibition of IRS1 may be a potential therapeutic target in ALL.",

keywords = "Acute lymphoblastic leukemia, Cell signaling, IGF1R/IRS1, NT157",

author = "{Rodrigues Alves}, {Ana Paula Nunes} and Fernandes, {Jaqueline Cristina} and Fenerich, {Bruna Alves} and Coelho-Silva, {Juan Luiz} and Scheucher, {Priscila Santos} and Sim{\~o}es, {Belinda Pinto} and Rego, {Eduardo Magalh{\~a}es} and Ridley, {Anne J.} and Machado-Neto, {Jo{\~a}o Agostinho} and Fabiola Traina",

year = "2019",

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doi = "10.1016/j.canlet.2019.04.030",

language = "English",

volume = "456",

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journal = "Cancer Letters",

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TY - JOUR

T1 - IGF1R/IRS1 targeting has cytotoxic activity and inhibits PI3K/AKT/mTOR and MAPK signaling in acute lymphoblastic leukemia cells

AU - Rodrigues Alves, Ana Paula Nunes

AU - Fernandes, Jaqueline Cristina

AU - Fenerich, Bruna Alves

AU - Coelho-Silva, Juan Luiz

AU - Scheucher, Priscila Santos

AU - Simões, Belinda Pinto

AU - Rego, Eduardo Magalhães

AU - Ridley, Anne J.

AU - Machado-Neto, João Agostinho

AU - Traina, Fabiola

PY - 2019/8/1

Y1 - 2019/8/1

N2 - The IGF1R/IRS1 signaling is activated in acute lymphoblastic leukemia (ALL)and can be targeted by the pharmacological inhibitors NT157 (IGF1R-IRS1/2 inhibitor)and OSI-906 (IGF1R/IR inhibitor). Here we investigate the cellular and molecular effects of NT157 and OSI-906 in ALL cells. NT157 and OSI-906 treatment reduced viability, proliferation and cell cycle progression in ALL cell lines. Similarly, in primary samples of patients with ALL, both OSI-906 and NT157 reduced viability, but only NT157 induced apoptosis. NT157 and OSI-906 did not show cytotoxicity in primary samples from healthy donor. NT157 and OSI-906 significantly decreased Jurkat cell migration, but did not modulate Namalwa migration. Consistent with the more potent effect of NT157 on cells, NT157 significantly modulated expression of 25 genes related to the MAPK signaling pathway in Jurkat cells, including oncogenes and tumor suppressor genes. Both compounds inhibited mTOR and p70S6K activity, but only NT157 inhibited AKT and 4-EBP1 activation. In summary, in ALL cells, NT157 has cytotoxic activity, whereas OSI-906 is cytostatic. NT157 has a stronger effect on ALL cells, and thus the direct inhibition of IRS1 may be a potential therapeutic target in ALL.

AB - The IGF1R/IRS1 signaling is activated in acute lymphoblastic leukemia (ALL)and can be targeted by the pharmacological inhibitors NT157 (IGF1R-IRS1/2 inhibitor)and OSI-906 (IGF1R/IR inhibitor). Here we investigate the cellular and molecular effects of NT157 and OSI-906 in ALL cells. NT157 and OSI-906 treatment reduced viability, proliferation and cell cycle progression in ALL cell lines. Similarly, in primary samples of patients with ALL, both OSI-906 and NT157 reduced viability, but only NT157 induced apoptosis. NT157 and OSI-906 did not show cytotoxicity in primary samples from healthy donor. NT157 and OSI-906 significantly decreased Jurkat cell migration, but did not modulate Namalwa migration. Consistent with the more potent effect of NT157 on cells, NT157 significantly modulated expression of 25 genes related to the MAPK signaling pathway in Jurkat cells, including oncogenes and tumor suppressor genes. Both compounds inhibited mTOR and p70S6K activity, but only NT157 inhibited AKT and 4-EBP1 activation. In summary, in ALL cells, NT157 has cytotoxic activity, whereas OSI-906 is cytostatic. NT157 has a stronger effect on ALL cells, and thus the direct inhibition of IRS1 may be a potential therapeutic target in ALL.

KW - Acute lymphoblastic leukemia

KW - Cell signaling

KW - IGF1R/IRS1

KW - NT157

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SN - 0304-3835

VL - 456

SP - 59

EP - 68

JO - Cancer Letters

JF - Cancer Letters

ER -

IGF1R/IRS1 targeting has cytotoxic activity and inhibits PI3K/AKT/mTOR and MAPK signaling in acute lymphoblastic leukemia cells

Abstract

Keywords

UN SDGs

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