Mannose-6-Phosphate Isomerase Functional Status Shapes a Rearrangement in the Proteome and Degradome of Mannose-Treated Melanoma Cells

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