Mannose-6-Phosphate\nIsomerase Functional Status Shapes\na Rearrangement in the Proteome and Degradome of Mannose-Treated Melanoma\nCells

Metabolic reprogramming is a ubiquitous feature of transformed\ncells, comprising one of the hallmarks of cancer and enabling neoplastic\ncells to adapt to new environments. Accumulated evidence reports on\nthe failure of some neoplastic cells to convert mannose-6-phosphate\ninto fructose-6-phosphate, thereby impairing tumor growth in cells\ndisplaying low levels of mannose-6-phosphate isomerase (MPI). Thus,\nwe performed functional analyses and profiled the proteome landscape\nand the repertoire of substrates of proteases (degradome) of melanoma\ncell lines with distinct mutational backgrounds submitted to treatment\nwith mannose. Our results suggest a significant rearrangement in the\nproteome and degradome of melanoma cell lines upon mannose treatment\nincluding the activation of catabolic pathways (such as protein turnover)\nand differences in protein N-terminal acetylation. Even though MPI\nprotein abundance and gene expression status are not prognostic markers,\nperturbation in the network caused by an exogenous monosaccharide\nsource (i.e., mannose) significantly affected the downstream interconnected\nbiological circuitry. Therefore, as reported in this study, the proteomic/degradomic\nmapping of mannose downstream effects due to the metabolic rewiring\ncaused by the functional status of the MPI enzyme could lead to the\nidentification of specific molecular players from affected signaling\ncircuits in melanoma.