Descriptive Proteome Analysis to Investigate Context-Dependent
Treatment Responses to OXPHOS Inhibition in Colon Carcinoma Cells
Grown as Monolayer and Multicellular Tumor Spheroids
Posted on 2020-07-06 - 21:31
We have previously identified selective
upregulation of the mevalonate
pathway genes upon inhibition of oxidative phosphorylation (OXPHOS)
in quiescent cancer cells. Using mass spectrometry-based proteomics,
we here investigated whether these responses are corroborated on the
protein level and whether proteomics could yield unique insights into
context-dependent biology. HCT116 colon carcinoma cells were cultured
as monolayer cultures, proliferative multicellular tumor spheroids
(P-MCTS), or quiescent (Q-MCTS) multicellular tumor spheroids and
exposed to OXPHOS inhibitors: nitazoxanide, FCCP, oligomycin, and
salinomycin or the HMG-CoA-reductase inhibitor simvastatin at two
different doses for 6 and 24 h. Samples were processed using an in-depth
bottom-up proteomics workflow resulting in a total of 9286 identified
protein groups. Gene set enrichment analysis showed profound differences
between the three cell systems and confirmed differential enrichment
of hypoxia, OXPHOS, and cell cycle progression-related protein responses
in P-MCTS and Q-MCTS. Treatment experiments showed that the observed
drug-induced alterations in gene expression of metabolically challenged
cells are not translated directly to the protein level, but the results
reaffirmed OXPHOS as a selective vulnerability of quiescent cancer
cells. This work provides rationale for the use of deep proteome profiling
to identify context-dependent treatment responses and encourages further
studies investigating metabolic processes that could be co-targeted
together with OXPHOS to eradicate quiescent cancer cells.
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Steinmetz, Julia; Senkowski, Wojciech; Lengqvist, Johan; Rubin, Jenny; Ossipova, Elena; Herman, Stephanie; et al. (2020). Descriptive Proteome Analysis to Investigate Context-Dependent
Treatment Responses to OXPHOS Inhibition in Colon Carcinoma Cells
Grown as Monolayer and Multicellular Tumor Spheroids. ACS Publications. Collection. https://doi.org/10.1021/acsomega.0c01419