Proteomics and degradomics applied to the study of the effects of mannose in Melanoma

• Grant number: 22/15421-0
• Support Opportunities: Regular Research Grants
• Start date: July 01, 2023
• End date: December 31, 2025
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: André Zelanis Palitot Pereira
• Grantee: André Zelanis Palitot Pereira
• Host Institution: Instituto de Ciência e Tecnologia (ICT). Universidade Federal de São Paulo (UNIFESP). Campus São José dos Campos. São José dos Campos , SP, Brazil
• Associated researchers: Claudia Barbosa Ladeira de Campos ; Flávio Vieira Loures ; Roger Chammas ; Silvina Odete Bustos

Abstract

The high energy demand imposed by the oncogenic process has significant consequences on the metabolism of transformed cells, as well as having a significant impact on diagnostic methods and therapies associated with the treatment of neoplasms. Mannose is an epimer of glucose that is internalized through the same transporters. Recent work using tumor cell lines demonstrated that this hexose accumulates in cells in the form of the intermediate mannose-6-phosphate (M6P), due to the low expression of the enzyme phosphomannose isomerase (PMI), which converts M6P into fructose-6-phosphate (F6P ), an intermediate of the glycolytic pathway. This feature significantly impacts glucose metabolism via the glycolytic pathway, the tricarboxylic acid cycle, and the pentose phosphate pathway. Recent data from our group indicate that the metabolic stress resulting from the administration of mannose to metastatic human melanoma cell lines results in a decrease in the growth rate, as well as in the activation of lysosomal degradation pathways and, possibly, of autophagy. In this context, the main objective of this project is to evaluate the effects of mannose administration on the cellular proteome of human and murine melanoma cell lines, as well as on the substrate repertoire of activated proteases (degradome). Also within the scope of this proposal is the evaluation of in vivo tumorigenesis in animals submitted to the injection of melanoma cells followed by the administration of mannose. Cellular models comprising distinct metabolic/mitogenic phenotypes (mutant B-Raf, A375, and non-mutant strain, WM 1366 strain, respectively) will be used, as well as a paired cell model composed of a murine melanocyte (Melan-a) and a metastatic strain (B16-F10). It is expected to correlate the results obtained with possible biological pathways relevant to the oncogenic process. From a therapeutic point of view, the results obtained will allow the elucidation of fundamental molecular aspects that may subsidize the increase of clinical intervention strategies using this hexose (mannose) associated with therapies already used for the treatment of human melanoma. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

RACORTI, NATHALIA DE VASCONCELLOS; MARTINELLI, MATHEUS; BUSTOS, SILVINA ODETE; SALARDANI, MURILO; CAMACHO, MAURICIO FROTA; BARCICK, UILLA; LIMA, LUIS ROBERTO FONSECA; JEDLICKA, LETICIA DIAS LIMA; DE CAMPOS, CLAUDIA BARBOSA LADEIRA; VALENTE, RICHARD HEMMI; et al. "Mannose-6-Phosphate Isomerase Functional Status Shapes a Rearrangement in the Proteome and Degradome of Mannose-Treated Melanoma Cells" (vol 23,pg 5177, 2024). JOURNAL OF PROTEOME RESEARCH, v. N/A, p. 1-pg., 2024-11-26. (21/05087-3, 22/15421-0, 19/10855-0, 23/05715-0)

SALARDANI, MURILO; BARCICK, UILLA; ZELANIS, ANDRE. Proteolytic signaling in cancer. EXPERT REVIEW OF PROTEOMICS, v. 20, n. 12, p. 11-pg., 2023-10-29. (21/05087-3, 22/15421-0)