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Nrf2‐Keap1 pathway does not have an important role in cisplatin resistance in neuroblastoma (655.8)
Author(s) -
Tanoshima Reo,
Yang MingDong,
Dalvi Pooja,
Wu Alex,
Matsuda Kensuke,
Zhang Libo,
Fujii Hisaki,
Baruchel Sylvain,
Harper Patricia,
Ito Shinya
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.655.8
Subject(s) - cisplatin , gene knockdown , keap1 , gclc , chemistry , small interfering rna , cancer research , microbiology and biotechnology , transcription factor , biology , downregulation and upregulation , biochemistry , apoptosis , transfection , gene , genetics , chemotherapy
Drug resistance is one of the major causes of treatment failure in neuroblastoma (NB). Cisplatin is one of the key chemotherapeutic agents for NB. Nuclear factor erythroid 2‐like‐2 (Nrf2) is a transcription factor that regulates anti‐oxidative stress enzymes and drug transporters, negatively regulated by Keap1 (kelch‐like ECH‐associated protein 1). Loss‐of‐function mutations of Keap1 gene and subsequent Nrf2 activation have been shown to be a mechanism of cisplatin resistance in adult cancers. We conducted this study to clarify the role of Nrf2‐Keap1 pathway in cisplatin resistance in NB. We investigated the basal activity of Nrf2 in nine NB cell lines (IMR‐32, LAN5, CHLA‐15, SH‐SY5Y, CHLA‐20, SKN‐FI, SK‐N‐BE(2), BE(2)C, CHLA‐90) using Antioxidant Response Element luciferase reporter assay. No cell lines had high reporter activities. In order to evaluate whether cisplatin activates Nrf2, we analyzed the mRNA expression of Nrf2 and its target genes (Glutamate‐Cysteine Ligase, Modifier Subunit: GCLM and NAD(P)H Dehydrogenase, Quinone 1: NQO1) after 24h treatment with cisplatin. In this experiment, we identified CHLA‐90 as one of the 3 cell lines, which showed high induction of Nrf2 target genes upon cisplatin exposure. However, knockdown of Nrf2 expression by small interfering RNA did not improve MTT assay‐measured dose‐response survival rate of CHLA‐90 with cisplatin treatment. We conclude that the Nrf2‐Keap1 pathway does not necessarily play an important role in cisplatin resistance in NB cells. Grant Funding Source : Supporter by CIHR, TCCSG, and Joseph M. West Family Memorial Fund