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.

Abstract

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.

• Authors: Chih-Cheng Chen, Chia-Bao Chu, Ko-Jiunn Liu, Chi-Ying F Huang, Jang-Yang Chang, Wen-Yu Pan, Huang-Hui Chen, Yun-Hsia Cheng, Kuan-Der Lee, Miao-Fen Chen, Ching-Chuan Kuo, Li-Tzong Chen
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 86 Issue 7 Pg. 872-87 (Oct 01 2013) ISSN: 1873-2968 [Electronic] England
• PMID: 23933386 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• IL6 protein, human
• Interleukin-6
• NF-E2-Related Factor 2
• NFE2L2 protein, human
• Organoplatinum Compounds
• RNA, Small Interfering
• Oxaliplatin
• 20-Hydroxysteroid Dehydrogenases
• 3 alpha-beta, 20 beta-hydroxysteroid dehydrogenase

Topics

• 20-Hydroxysteroid Dehydrogenases (genetics, metabolism)
• Antineoplastic Agents (pharmacology)
• Antioxidant Response Elements (drug effects, genetics)
• Drug Resistance, Neoplasm (drug effects, genetics)
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic (drug effects)
• Gene Knockdown Techniques
• Humans
• Interleukin-6 (metabolism, pharmacology)
• NF-E2-Related Factor 2 (genetics, metabolism)
• Organoplatinum Compounds (pharmacology)
• Oxaliplatin
• RNA, Small Interfering
• Signal Transduction (drug effects)
• Stomach Neoplasms (drug therapy, genetics, metabolism)
• Tumor Cells, Cultured