title: Can hyperthermic intraperitoneal chemotherapy efficiency be improved by blocking the DNA repair factor COP9 signalosome?
abstract: OBJECTIVE
  A frequently used chemotherapeutic agent in hyperthermic intraperitoneal chemotherapy (HIPEC) is mitomycin C (MMC) which induces DNA damage and apoptosis in tumor cells. In addition, MMC activates DNA damage response (DDR) leading to repair mechanisms counteracting the effect of chemotherapy. COP9 signalosome (CSN) positively influences the DDR pathway by its intrinsic deneddylating and associated kinase activities. In an in vitro HIPEC model, we studied the impact of curcumin, an inhibitor of CSN-associated kinases, and of the microRNA (miRNA) let-7a-1, an inhibitor of CSN subunit expression, on the MMC-induced apoptosis in human HT29 colon cancer cells.
  
  
  METHODS
  Cells were incubated at 37 °C and indicated concentrations of MMC in a medium preheated to 42 °C as under HIPEC conditions for 1 or 4 h. HT29 cells were cotreated with 50 μM curcumin or transfected with let-7a-1 miRNA mimic. After incubation, cells were analyzed by Western blotting, densitometry, and caspase-3 ELISA.
  
  
  RESULTS
  An increase of CSN subunits in response to MMC treatment was detected. Apoptosis was only measured after 4 h with 50 μM MMC. MMC-induced apoptosis was elevated by cotreatment with curcumin. Transfection of HT29 cells with let-7a-1 reduced the expression of tested CSN subunits associated with the accumulation of the pro-apoptotic factors p27 and p53.
  
  
  CONCLUSIONS
  In response to MMC treatment, the CSN is elevated as a regulator of DDR retarding apoptosis in tumor cells. The therapeutic effect of HIPEC can be increased by inhibiting CSN-associated kinases via curcumin or by blocking CSN expression with let-7a-1 miRNA.
authors.affiliation: Division of Molecular Biology, Department of General, Visceral, Vascular and Thoracic Surgery, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Feist
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Huang
authors.forename: Joachim M
authors.initials: JM
authors.lastname: Müller
authors.forename: Beate
authors.initials: B
authors.lastname: Rau
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Dubiel
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D000075686:COP9 Signalosome Complex; D053148:Caspase 3 / Q000378:metabolism; D003474:Curcumin / Q000008:administration & dosage* / Q000494:pharmacology; D004249:DNA Damage / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D019073:HT29 Cells; D006801:Humans; D006979:Hyperthermia, Induced; D035683:MicroRNAs / Q000008:administration & dosage* / Q000494:pharmacology; D016685:Mitomycin / Q000008:administration & dosage* / Q000494:pharmacology; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors*; D010447:Peptide Hydrolases; D010534:Peritoneal Neoplasms / Q000188:drug therapy*
chemical_list: D000970:Antineoplastic Agents; D035683:MicroRNAs; D046912:Multiprotein Complexes; C487931:mirnlet7 microRNA, human; D016685:Mitomycin; D010447:Peptide Hydrolases; D000075686:COP9 Signalosome Complex; D053148:Caspase 3; D003474:Curcumin
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