RPN2 gene confers docetaxel resistance in breast cancer.
Drug resistance acquired by cancer cells has led to treatment failure. To understand the regulatory network underlying docetaxel resistance in breast cancer cells and to identify molecular targets for therapy, we tested small interfering RNAs (siRNAs) against 36 genes whose expression was elevated in human nonresponders to docetaxel for the ability to promote apoptosis of docetaxel-resistant human breast cancer cells (MCF7-ADR cells). The results indicate that the downregulation of the gene encoding ribophorin [corrected] II (RPN2), which is part of an N-oligosaccharyl transferase complex, most efficiently induces apoptosis of MCF7-ADR cells in the presence of docetaxel. RPN2 silencing induced reduced glycosylation of the P-glycoprotein, as well as decreased membrane localization, thereby sensitizing MCF7-ADR cells to docetaxel. Moreover, in vivo delivery of siRNA specific for RPN2 markedly reduced tumor growth in two types of models for drug resistance. Thus, RPN2 silencing makes cancer cells hypersensitive response to docetaxel, and RPN2 might be a new target for RNA interference-based therapeutics against drug resistance.
Honma
Kimi
K
Section for Studies on Metastasis, Japanese National Cancer Center Research Institute, 1-1, Tsukiji, 5-chome, Chuo-ku, Tokyo 104-0045, Japan.
Iwao-Koizumi
Kyoko
K
Takeshita
Fumitaka
F
Yamamoto
Yusuke
Y
Yoshida
Teruhiko
T
Nishio
Kazuto
K
Nagahara
Shunji
S
Kato
Kikuya
K
Ochiya
Takahiro
T
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D045744:Cell Line, Tumor; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006602:Hexosyltransferases; D006801:Humans; D020287:In Situ Nick-End Labeling; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D043823:Taxoids / Q000494:pharmacology*
D000970:Antineoplastic Agents; D034741:RNA, Small Interfering; D043823:Taxoids; D000077143:Docetaxel; D006602:Hexosyltransferases; C517590:RPN2 protein, human; D046988:Proteasome Endopeptidase Complex