Full text
| |
| Author(s): |
Leonardo Luís Artico
Total Authors: 1
|
| Document type: | Doctoral Thesis |
| Press: | Campinas, SP. |
| Institution: | Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia |
| Defense date: | 2023-08-18 |
| Examining board members: |
José Andrés Yunes;
Carmen Haider;
Céline Marques Pinheiro;
Fabio Papes;
Giselle Zenker Justo
|
| Advisor: | José Andrés Yunes |
| Abstract | |
Acute Lymphoblastic Leukemia (ALL) is the most common childhood cancer. Although survival rates for pediatric ALL have reached around 90% in the last decade, still approximately 20 to 30% of patient’s relapse, and some experiencing long-term sequelae of therapy including a second malignancy. Therefore, new targets and therapeutic strategies are needed. Insulin and insulin-like growth factors (IGFs) are mitogenic and pro-survival factors for many different cell types, including ALL. Circulating IGFs are bound by IGF Binding Proteins (IGFBP) 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 has been shown to bind the IGF1 receptor (IGF1R). The role of IGFBP7 in cancer is controversial: in some tumors it was related to oncogene while in others as a tumor suppressor. In childhood ALL, higher IGFBP7 expression levels were associated with worse prognosis. Here we first show that IGFBP7 exerts mitogenic and pro-survival autocrine effects on ALL, which is 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. Our data reveals that IGFBP7 prolongs the surface retention of the IGF1R under insulin/IGF1 stimulation, resulting in sustained phosphorylation of IGF1R, IRS, AKT, and ERK1/2. Second, we also show that sustained activation of the IGF1R-PI3K-Akt axis, mediated by IGFBP7, concurs to GLUT1 upregulation, which enhance energy metabolism and increases glycolytic metabolism in B-cell precursor ALL (BCP-ALL). Both IGFBP7 neutralization with a monoclonal antibody (clone C311) as well as pharmacological inhibition of PI3K-Akt pathway abrogates this effect, restoring the physiological levels of GLUT1 on the cell surface. In conclusion, IGFBP7 plays an oncogenic role in ALL by promoting the perdurance of IGF1R at the cell surface, prolonging insulin/IGFs stimulation and enhancing glycolytic metabolism through the IGF1R-Akt-GLUT1 axis. The cellular and metabolic effects described here may offer an additional mechanistic explanation for the strong negative impact seen in ALL cells in vitro and in vivo after the knockdown or antibody neutralization of IGFBP7, revealing a hitherto unknown role for IGFBP7 in ALL, and opening doors for future investigations (AU) | |
| FAPESP's process: | 19/04943-3 - IGFBP7 action on TGFb/p53 pathways and corticoids resistance in Acute Lymphoblastic Leukemia |
| Grantee: | Leonardo Luís Artico |
| Support Opportunities: | Scholarships in Brazil - Doctorate |