Gene expression profiling for analysis acquired oxaliplatin resistant factors in human gastric carcinoma TSGH-S3 cells: the role of IL-6 signaling and Nrf2/AKR1C axis identification.
Oxaliplatin treatment is a mainstay of treatment for advanced gastrointestinal tract cancer, but the underlying mechanisms of acquired oxaliplatin resistance remain largely obscured. We previously demonstrated that increased DNA repair capacity and copper-transporting ATPase 1 (ATP7A) level contributed to oxaliplatin resistance in the human gastric carcinoma cell line TSGH-S3 (S3). In the present study, we applied gene array technology to identify additional resistance factors in S3 cells. We found that interleukin-6 (IL-6), aldo-keto reductase 1C1 (AKR1C1), and AKR1C3 are the top 3 upregulated genes in S3 cells when compared with parent TSGH cells. Despite a higher level of endogenous IL-6 in S3, IL-6 receptor (IR-6R, gp-80, and gp-130) levels were similar between TSGH and S3 cells. The addition of exogenous IL-6, IL-6 targeted siRNA, or neutralizing antibodies neither affected Stat3 activation, a downstream target of IL-6, nor changed oxaliplatin sensitivity in S3 cells. However, manipulation of AKR1C activity with siRNA or AKR1C inhibitors significantly reversed oxaliplatin resistance. AKR1Cs are classical antioxidant response element (ARE) genes that can be transcriptionally upregulated by nuclear factor erythroid 2-related factor 2 (Nrf2). Knockdown of Nrf2 not only decreased the levels of AKR1C1, AKR1C2, and AKR1C3 mRNA and protein but also reversed oxaliplatin resistance in S3 cells. Taken together, these results suggest that activation of the Nrf2/AKR1C axis may contribute to oxaliplatin resistance in S3 cells but that the IL-6 signaling pathway did not contribute to resistance. Manipulation of Nrf2/AKR1Cs activity may be useful for management of oxaliplatin-refractory gastric cancers.
Department of Hematology and Oncology, Chang Gung Memorial Hospital at Chiayi, Chiayi, Taiwan, ROC; Chang Gung University, College of Medicine, Chang Gung Institute of Technology, Chiayi, Taiwan, ROC; Graduate Institute of Clinical Medical Sciences, Chang Gung University, Tao-Yuan, Taiwan, ROC.
Chih-Cheng
CC
Chen
Chia-Bao
CB
Chu
Ko-Jiunn
KJ
Liu
Chi-Ying F
CY
Huang
Jang-Yang
JY
Chang
Wen-Yu
WY
Pan
Huang-Hui
HH
Chen
Yun-Hsia
YH
Cheng
Kuan-Der
KD
Lee
Miao-Fen
MF
Chen
Ching-Chuan
CC
Kuo
Li-Tzong
LT
Chen
D015089:20-Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology; D061745:Antioxidant Response Elements / Q000187:drug effects / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism* / Q000494:pharmacology; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; C508600:IL6 protein, human; D015850:Interleukin-6; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D009944:Organoplatinum Compounds; D034741:RNA, Small Interfering; D000077150:Oxaliplatin; D015089:20-Hydroxysteroid Dehydrogenases; C115140:3 alpha-beta, 20 beta-hydroxysteroid dehydrogenase
AKR1Cs; ARE; Acquired resistance; ERCC-1; ERK; FFA; GCLC; GCLM; GI; GR; GST; HIF-1α; HO-1; IL -6R/gp130; IL -6R/gp80; IL-6; IL-6 receptor α subunit; IL-6 receptor β subunit; IL-6 signaling; JAK1; JAK2; Janus kinase 1; Janus kinase 2; MAPK; MCA; NAD(P)H:quinone oxidoreductase; NQO-1; Nrf2; Nrf2/AKR1C axis; Oxaliplatin; PI3K; PPTH; S3; STAT3; TR; TYK2; aldo-keto reductase family members (e.g. AKR1C1, AKR1C2, or AKR1C3); an oxaliplatin-resistant human gastric carcinoma cell line (TSGH-S3); antioxidant response element; cis-diamminedichloroplatinum(II) (CDDP); cisplatin; excision repair cross-complementing-1; extracellular signal-related kinase; flufenamic acid; gastrointestinal tract; glutathione S-transferase; glutathione reductase; heme oxygenase-1; hypoxia-inducible factor-1α; interleukin-6; mitogen-activated protein kinase; nuclear factor erythroid 2-related factor 2; phenolphthalein; phosphatidylinositol 3-kinase; signal transducer and activator of transcription 3; thioredoxin reductase; tyrosine kinase 2; α-methylcinnamic acid; γ-glutamyl cysteine synthetase catalytic subunit; γ-glutamyl cysteine synthetase modifier subunit