TRAP1, a novel mitochondrial chaperone responsible for multi-drug resistance and protection from apoptotis in human colorectal carcinoma cells.
TRAP1 is a component of a pro-survival mitochondrial pathway up-regulated in tumor cells. The evaluation of TRAP1 expression in 26 human colorectal carcinomas showed up-regulation in 17/26 tumors. Accordingly, TRAP1 levels were increased in HT-29 colorectal carcinoma cells resistant to 5-fluorouracil, oxaliplatin and irinotecan. Thus, we investigated the role of TRAP1 in multi-drug resistance in human colorectal cancer. Interestingly, TRAP1 overexpression leads to 5-fluorouracil-, oxaliplatin- and irinotecan-resistant phenotypes in different neoplastic cells. Conversely, the inhibition of TRAP1 activity by TRAP1 ATPase antagonist, shepherdin, increased the sensitivity to oxaliplatin and irinotecan in colorectal carcinoma cells resistant to the single agents. These results suggest that the increased expression of TRAP1 could be part of a pro-survival pathway responsible for multi-drug resistance.
Costantino
Eleonora
E
Clinical Oncology Unit, Department of Medical Sciences, University of Foggia, Viale Pinto 1, 71100 Foggia, Italy.
Maddalena
Francesca
F
Calise
Serena
S
Piscazzi
Annamaria
A
Tirino
Virginia
V
Fersini
Alberto
A
Ambrosi
Antonio
A
Neri
Vincenzo
V
Esposito
Franca
F
Landriscina
Matteo
M
D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019073:HT29 Cells; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D010446:Peptide Fragments / Q000494:pharmacology; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D014162:Transfection; D015854:Up-Regulation
D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D009944:Organoplatinum Compounds; D010446:Peptide Fragments; D012333:RNA, Messenger; C092306:TRAP1 protein, human; C503112:shepherdin; D000077150:Oxaliplatin; D000077146:Irinotecan; D005472:Fluorouracil; D002166:Camptothecin