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

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

Research output: Contribution to journalArticle

23 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)872-887
Number of pages16
JournalBiochemical Pharmacology
Volume86
Issue number7
DOIs
Publication statusPublished - 2013
Externally publishedYes

Fingerprint

oxaliplatin
Gene Expression Profiling
Gene expression
Interleukin-6
Stomach
Carcinoma
Genes
Small Interfering RNA
Chemical activation
Antioxidant Response Elements
Interleukin-6 Receptors
Gastrointestinal Neoplasms
R Factors
Neutralizing Antibodies

Keywords

  • Acquired resistance
  • IL-6 signaling
  • Nrf2/AKR1C axis
  • Oxaliplatin

ASJC Scopus subject areas

  • Pharmacology
  • Biochemistry

Cite this

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. / Chen, Chih Cheng; Chu, Chia Bao; Liu, Ko Jiunn; Huang, Chi Ying F; Chang, Jang Yang; Pan, Wen Yu; Chen, Huang Hui; Cheng, Yun Hsia; Lee, Kuan Der; Chen, Miao Fen; Kuo, Ching Chuan; Chen, Li Tzong.

In: Biochemical Pharmacology, Vol. 86, No. 7, 2013, p. 872-887.

Research output: Contribution to journalArticle

Chen, Chih Cheng ; Chu, Chia Bao ; Liu, Ko Jiunn ; Huang, Chi Ying F ; Chang, Jang Yang ; Pan, Wen Yu ; Chen, Huang Hui ; Cheng, Yun Hsia ; Lee, Kuan Der ; Chen, Miao Fen ; Kuo, Ching Chuan ; Chen, Li Tzong. / 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. In: Biochemical Pharmacology. 2013 ; Vol. 86, No. 7. pp. 872-887.
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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.",
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AU - Liu, Ko Jiunn

AU - Huang, Chi Ying F

AU - Chang, Jang Yang

AU - Pan, Wen Yu

AU - Chen, Huang Hui

AU - Cheng, Yun Hsia

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AU - Kuo, Ching Chuan

AU - Chen, Li Tzong

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AB - 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.

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