Systematic analysis of synergistic proteome modulations in a drug combination of cisplatin and MLN4924

ABSTRACT: Chemotherapeutic treatment regimens often take advantage of synergistic effects of drug combinations. Anticipating that synergistic effects on cell biological level likely manifest on proteome level, the analysis of proteome modulations represents an appropriate strategy to study drug combinations on molecular level. More specifically, the detection of single proteins exhibiting synergistic abundance changes could be helpful to shed light on key molecules, which contribute in mechanisms facilitating the synergistic interaction and therefore represent potential target for specific therapeutic approaches. In the reported study, we investigated the drug combination of cisplatin and the neddylation inhibitor MLN4924 in HCT-116 cells via cell biological analyses and mass spectrometry-based quantitative proteomics. From 1,789 proteins quantified with two unique peptides, activated RNA polymerase II transcriptional coactivator p15 (SUB1) was highlighted as most synergistically regulated protein using a synergistic scoring approach. Western blotting and analyses of cellular processes associated with this protein (DNA damage, oxidative stress and apoptosis) revealed supporting evidence for the synergistic regulation. Whereas the distinct role of SUB1 in the investigated drug combination needs to be elucidated in future studies, the presented results demonstrated the benefit and feasibility of synergistic scoring of proteome alterations to highlight proteins that likely contribute to the underlying molecular mechanisms of synergistic effects.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Dominik Andre Meger  

LAB HEAD: Dominik Andre Megger

PROVIDER: PXD009185 | Pride | 2018-10-02

REPOSITORIES: Pride