Increased expression of Nrf2/ARE-dependent anti-oxidant proteins in tamoxifen-resistant breast cancer cells.
Acquired resistance to tamoxifen (TAM) is a serious therapeutic problem in breast cancer patients. In this study, we found that the expressions of anti-oxidant proteins (gamma-glutamylcysteine ligase heavy chain (gamma-GCL h), heme oxygenase-1, thioredoxin and peroxiredoxin1) in TAM-resistant MCF-7 (TAMR-MCF-7) cells were higher than control MCF-7 cells. Molecular analyses using antioxidant response element (ARE)-containing reporters and gel-shift supported the critical role of NF-E2-related factor2 (Nrf2)/ARE in the overexpression of antioxidant proteins in TAMR-MCF-7 cells. Intracellular peroxide production was significantly decreased in TAMR-MCF-7 cells and TAM resistance was partially reversed by Nrf2 siRNA. The basal phosphorylation of extracellular signal-regulated kinase (ERK) and p38 kinase were increased in the TAMR-MCF-7 cells and the inhibition of ERK significantly decreased the activity of minimal ARE reporter and gamma-GCL h protein expression in TAMR-MCF-7 cells. However, exposure of TAMR-MCF-7 cells to 17-beta-estradiol or ICI-182,780 did not significantly change gamma-GCL h expression. These results suggest that the persistent activation of Nrf2/ARE is critical for the enhanced expression of anti-oxidant proteins in TAM-resistant breast cancer cells and the pathway of ERK, but not of estrogen receptor signaling are involved in the up-regulation of Nrf2/ARE.
Kim
Sang Kyum
SK
College of Pharmacy and Research Center for Transgenic Cloned Pigs, Chungnam National University, Daejeon, South Korea.
Yang
Jin Won
JW
Kim
Mi Ra
MR
Roh
Sang Hee
SH
Kim
Hyung Gyun
HG
Lee
Kwang Youl
KY
Jeong
Hye Gwang
HG
Kang
Keon Wook
KW
D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D000975:Antioxidants / Q000378:metabolism*; D001483:Base Sequence; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005721:Glutamate-Cysteine Ligase / Q000378:metabolism; D006801:Humans; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen / Q000378:metabolism; D015398:Signal Transduction; D013629:Tamoxifen / Q000494:pharmacology*
D018931:Antineoplastic Agents, Hormonal; D000975:Antioxidants; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495635:NFE2L2 protein, human; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen; D013629:Tamoxifen; D005721:Glutamate-Cysteine Ligase