Systematic Protein Level Regulation via Degradation Machinery Induced by Genotoxic Drugs

• Published in: Journal of proteome research 2016-01, Vol.15 (1), p.205-215
• Main Authors: Kume, Kohei, Ishida, Kazushige, Ikeda, Miyuki, Takemoto, Kazuhiro, Shimura, Tsutomu, Young, Lynn, Nishizuka, Satoshi S
• Format: Article
• Language: English
• Subjects: Apoptosis; Camptothecin - analogs & derivatives; Camptothecin - toxicity; Cisplatin - toxicity; DNA Damage; Fluorouracil - toxicity; HCT116 Cells; Humans; Leupeptins - pharmacology; Mutagens - toxicity; Proteasome Endopeptidase Complex - metabolism; Proteasome Inhibitors - pharmacology; Proteolysis - drug effects; Proteome - metabolism
• ISSN: 1535-3893; 1535-3907
• DOI: 10.1021/acs.jproteome.5b00759

In this study we monitored protein dynamics in response to cisplatin, 5-fluorouracil, and irinotecan with different concentrations and administration modes using “reverse-phase” protein arrays (RPPAs) in order to gain comprehensive insight into the protein dynamics induced by genotoxic drugs. Among 666 protein time-courses, 38% exhibited an increasing trend, 32% exhibited a steady decrease, and 30% fluctuated within 24 h after drug exposure. We analyzed almost 12,000 time-course pairs of protein levels based on the geometrical similarity by correlation distance (dCor). Twenty-two percent of the pairs showed dCor > 0.8, which indicates that each protein of the pair had similar dynamics. These trends were disrupted by a proteasome inhibitor, MG132, suggesting that the protein degradation system was activated in response to the drugs. Among the pairs with high dCor, the average dCor of pairs with apoptosis-related protein was significantly higher than those without, indicating that regulation of protein levels was induced by the drugs. These results suggest that the levels of numerous functionally distinct proteins may be regulated by common degradation machinery induced by genotoxic drugs.