Effect of cisplatin on proteasome activity

• Published in: Journal of inorganic biochemistry Vol. 153; pp. 253 - 258
• Main Authors: Tundo, G.R., Sbardella, D., Ciaccio, C., De Pascali, S., Campanella, V., Cozza, P., Tarantino, U., Coletta, M., Fanizzi, F.P., Marini, S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-12-2015
• Subjects: Acetylcysteine - analogs & derivatives; Acetylcysteine - pharmacology; Antineoplastic Agents - pharmacology; Cell Line, Tumor; Cisplatin; Cisplatin - pharmacology; Cysteine Proteinase Inhibitors - pharmacology; Drug Synergism; Humans; Lactacystin; Neuroblastoma; Proteasome; Proteasome Endopeptidase Complex - metabolism; Proteasome Inhibitors - pharmacology; Ubiquitination; Lactacystin; PMSF; DTT; UPS; Neuroblastoma; EDTA; ER; CP; RP; Cisplatin; Proteasome
• ISSN: 0162-0134; 1873-3344
• DOI: 10.1016/j.jinorgbio.2015.08.027

Cisplatin is a widely used chemotherapy drug which exerts cytotoxic activity by affecting both nuclear and cytosolic pathways. Herewith, we report, for the first time, that cisplatin inhibits proteasome activity in vitro. Cisplatin induces a dose dependent inhibition of the three enzymatic activities of proteasome (i.e., the chymotrypsin-like activity, the trypsin-like activity and the caspase-like activity). Moreover, cisplatin administration to neuroblastoma cells brings about a fast loss of proteasome particle activity, which is followed by a de novo synthesis of proteasome. Lastly, we report that the simultaneous administration of lactacystin and cisplatin enhances the cytotoxicity of cisplatin alone. The overall bulk of data opens to an intriguing scenario, concerning the biological effects of cisplatin in the control of cellular life, which goes beyond the well established genotoxic effect.
Cisplatin is a chemotherapy drug. We report that cisplatin inhibits in dose-dependent fashion the enzymatic proteasome activities. Cisplatin administration to neuroblastoma cells also brings about a loss of proteasome activity followed by proteasome de novo synthesis. Finally, the co-administration of lactacystin (specific proteasome inhibitor) and cisplatin enhances cisplatin cytotoxicity. [Display omitted]
•Cisplatin targets 20S proteasome activity in vitro.•All intracellular proteasome particles are inhibited by cisplatin.•Poly-ubiquitinated proteins accumulate in cisplatin treated cells.•Cisplatin and proteasome inhibitors cooperate.