Oxaliplatin resistance induced by ERCC1 up-regulation is abrogated by siRNA-mediated gene silencing in human colorectal cancer cells.
BACKGROUND
Oxaliplatin is used to treat patients with colorectal cancer (CRC); however, half the patients fail to benefit. The excision repair cross-complementing group-1 (ERCC1) gene was studied and it was hypothesized that its inducible expression contributes to cellular resistance.


METHODS
Thirty CRC cell lines were treated with oxaliplatin and sensitivity was determined by apoptosis. Four sensitive and resistant cell lines were analyzed for oxaliplatin effect on ERCC1 expression and two resistant cell lines were subjected to siRNA-mediated gene silencing.


RESULTS
There was no correlation of basal ERCC1 mRNA expression with response to oxaliplatin. ERCC1 mRNA was induced at 24, 48, and 72 hours (71-264%, p<0.05) and ERCC1 protein at 48 hours (123-521%, p<0.05) post-oxaliplatin treatment in resistant cells only. siRNA-mediated silencing of ERCC1 sensitized the CRC cells to oxaliplatin-induced apoptosis, and increased cleaved PARP.


CONCLUSIONS
ERCC1 gene expression is inducible, contributes to oxaliplatin resistance, and is reversible by targeted suppression of ERCC1, identifying ERCC1 as a potential target for drug development.
Seetharam
Raviraja N
RN
Department of Oncology, Montefiore Medical Center, Bronx, NY, USA.
Sood
Arjun
A
Basu-Mallick
Atrayee
A
Augenlicht
Leonard H
LH
Mariadason
John M
JM
Goel
Sanjay
S
D000970:Antineoplastic Agents / Q000494:pharmacology; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000628:therapy*; D003131:Combined Modality Therapy; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D004720:Endonucleases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D019073:HT29 Cells; D006801:Humans; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics*; D014162:Transfection; D015854:Up-Regulation
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D009944:Organoplatinum Compounds; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000077150:Oxaliplatin; C071447:ERCC1 protein, human; D004720:Endonucleases