Involvement of ribonucleotide reductase M1 subunit overexpression in gemcitabine resistance of human pancreatic cancer.
Pancreatic cancer is the most lethal of all solid tumors partially because of its chemoresistance. Although gemcitabine is widely used as a first selected agent for the treatment of this disease despite low response rate, molecular mechanisms of gemcitabine resistance in pancreatic cancer still remain obscure. The aim of this study is to elucidate the mechanisms of gemcitabine resistance. The 81-fold gemcitabine resistant variant MiaPaCa2-RG was selected from pancreatic cancer cell line MiaPaCa2. By microarray analysis between MiaPaCa2 and MiaPaCa2-RG, 43 genes (0.04%) were altered expression of more than 2-fold. The most upregulated gene in MiaPaCa2-RG was ribonucleotide reductase M1 subunit (RRM1) with 4.5-fold up-regulation. Transfection with RRM1-specific RNAi suppressed more than 90% of RRM1 mRNA and protein expression. After RRM1-specific RNAi transfection, gemcitabine chemoresistance of MiaPaCa2-RG was reduced to the same level of MiaPaCa2. The 18 recurrent pancreatic cancer patients treated by gemcitabine were divided into 2 groups by RRM1 levels. There was a significant association between gemcitabine response and RRM1 expression (p = 0.018). Patients with high RRM1 levels had poor survival after gemcitabine treatment than those with low RRM1 levels (p = 0.016). RRM1 should be a key molecule in gemcitabine resistance in human pancreatic cancer through both in vitro and clinical models. RRM1 may have the potential as predictor and modulator of gemcitabine treatment.
Nakahira
Shin
S
Department of Surgery and Clinical Oncology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
Nakamori
Shoji
S
Tsujie
Masanori
M
Takahashi
Yuji
Y
Okami
Jiro
J
Yoshioka
Shinichi
S
Yamasaki
Makoto
M
Marubashi
Shigeru
S
Takemasa
Ichiro
I
Miyamoto
Atsushi
A
Takeda
Yutaka
Y
Nagano
Hiroaki
H
Dono
Keizo
K
Umeshita
Koji
K
Sakon
Masato
M
Monden
Morito
M
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D016372:RNA, Antisense / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D012262:Ribonucleoside Diphosphate Reductase; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D015854:Up-Regulation; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D016372:RNA, Antisense; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; D003841:Deoxycytidine; C475286:RRM1 protein, human; D012262:Ribonucleoside Diphosphate Reductase; D000093542:Gemcitabine