Physiologic IGFBP7 levels prolong IGF1R activation in acute lymphoblastic leukemia

Autor(es)

Artico, Leonardo Luis ^{[1, 2]} ; Albertoni Laranjeira, Angelo Brunelli ^[1] ; Campos, Livia Weijenborg ^{[1, 2]} ; Correa, Juliana Ronchi ^{[1, 2]} ; Zenatti, Priscila Pini ^[1] ; Campello Carvalheira, Jose Barreto ^[3] ; Brambilla, Sandra Regina ^[3] ; Nowill, Alexandre Eduardo ^[4] ; Brandalise, Silvia Regina ^[1] ; Yunes, Jose Andres ^{[1, 5]}

Afiliação do(s) autor(es)

^[1] Ctr Infantil Boldrini, Campinas - Brazil

^[2] State Univ Capinas, Biol Inst, Grad Program Genet & Mol Biol, Campinas - Brazil

^[3] Univ Estadual Campinas, Fac Med Sci, Dept Clin Med, Campinas - Brazil

^[4] Univ Estadual Campinas, Fac Med Sci, Ctr Integrad Pesquisas Oncohematol Infancia, Campinas - Brazil

^[5] Univ Estadual Campinas, Fac Med Sci, Dept Genet Med, Campinas - Brazil

• Tipo de documento: Artigo Científico
• Fonte: BLOOD ADVANCES; v. 5, n. 18, p. 3633-3646, SEP 28 2021.
• Citações Web of Science: 0

Resumo

Insulin and insulin-like growth factors (IGFs) are mitogenic and prosurvival factors to many different cell types, including acute lymphoblastic leukemia (ALL). Circulating IGFs are bound by IGF binding proteins (IGFBPs) that regulate their action. IGFBP7 is an IGFBP-related protein (IGFBP-rP) that in contrast to other IGFBPs/IGFBP-rPs features higher affinity for insulin than IGFs and was shown to bind the IGF1 receptor (IGF1R) as well. The role of IGFBP7 in cancer is controversial: on some tumors, it functions as an oncogene, whereas in others, it functions as a tumor suppressor. In childhood ALL, higher IGFBP7 expression levels were associated with worse prognosis. Here we show that IGFBP7 exerts mitogenic and prosurvival autocrine effects on ALL cells that were dependent on insulin/IGF. IGFBP7 knockdown or antibody-mediated neutralization resulted in significant attenuation of ALL cell viability in vitro and leukemia progression in vivo. IGFBP7 was shown to prolong the surface retention of the IGF1R under insulin/IGF1 stimulation, resulting in sustained IGF1R, insulin receptor substrate 1 (IRS-1), protein kinase B (AKT), and extracellular signal-regulated kinase (ERK) phosphorylation. Conversely, the insulin receptor was readily internalized and dephosphorylated on insulin stimulation, despite IGFBP7 addition. The affinity of homodimeric IGF1R for insulin is reportedly >100 times lower than for IGF1. In the presence of IGFBP7, however, 25 ng/mL insulin resulted in IGF1R activation levels equivalent to that of 5 ng/mL IGF1. In conclusion, IGFBP7 plays an oncogenic role in ALL by promoting the perdurance of IGF1R at the cell surface, prolonging insulin/IGF stimulation. Predinical data demonstrate that IGFBP7 is a valid target for antibody-based therapeutic interventions in ALL. (AU)

• Processo FAPESP: 14/20015-5 - Sinalização aberrante do IL7R e leucemogênese: ciência básica e pesquisa de potencial terapia
• Beneficiário: José Andrés Yunes
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 12/12802-1 - Mutações cooperantes, caracterização funcional e anticorpos contra o mutante do IL7R na leucemia linfóide aguda
• Beneficiário: José Andrés Yunes
• Modalidade de apoio: Auxílio à Pesquisa - Regular