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iASPP-Mediated ROS Inhibition Drives 5-Fu Resistance Dependent on Nrf2 Antioxidative Signaling Pathway in Gastric Adenocarcinoma

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Abstract

Aims

Inhibitor for the apoptosis-stimulating protein of p53 (iASPP) has been reported to be correlated with 5-fluorouracil (5-Fu) resistance in renal cell carcinoma. Here, we uncover mechanisms of iASPP-Nrf2-ROS regulation of 5-Fu resistance which are important for the development of alternative treatment strategies for gastric adenocarcinoma treatment.

Methods

We analyzed iASPP and Nrf2 through TCGA RNA-seq data, UALCAN analysis, and cBioPortal datasets. Intracellular ROS generation was determined by 2′,7′-dichloro-fluorescin diacetate staining. Transwell was used to evaluate the invasion. The expression of iASPP, Nrf2, HO-1, and GSTP1 was tested using western blot.

Results

We found that iASPP KD led to an apparent 5-Fu-induced ROS accumulation in MGC803 and SCG790 cells. Accompanied by iASPP KD, Nrf2 was markedly decreased. iASPP-induced ROS inhibition relies on Nrf2, and due to both knocked down iASPP and Nrf2, the level of ROS did not show an obvious difference with Nrf2 KD solely. Similarly, iASPP KD failed to enhance the Nrf2 KD-mediated ROS accumulation after 5-Fu treatment, suggesting that iASPP-induced antioxidative effects related to 5-Fu resistance are partially dependent on Nrf2. Also, the combination of iASPP KD and Nrf2 KD did not show any synergistic effect on apoptosis after 5-Fu treatment in MGC803 and SCG790 cells. Further studies revealed that iASPP KD or Nrf2 KD could decrease the expression of HO-1 and GSTP1.

Conclusions

Our data highlight that iASPP plays a crucial role in the inhibition of 5-Fu-induced apoptosis resistance by removing ROS accumulation in gastric adenocarcinoma, and that the removal of ROS induced by iASPP is Nrf2 signaling dependent.

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Acknowledgments

This work was supported by funds from the National Natural Science Foundation of China (81602721).

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Authors and Affiliations

  1. Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China

    Lu Wen, Shengli Yang, Pindong Li, Renwang Chen, Qiushuang Wang & Jianli Hu

  2. Rogel Cancer Center, The University of Michigan, Ann Arbor, MI, USA

    Bashir Kaspo

  3. Traditional Chinese Medicine Department, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China

    Heng Fan

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  1. Lu Wen
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  2. Shengli Yang
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Contributions

LW, HF, and JH contributed to conception and design. SY, PL, and RC developed the methodology. LW contributed to acquisition of data. LW, SY, and QW contributed to analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis). LW, BK, and JH wrote, reviewed, and/or revised the manuscript. HF contributed to administrative, technical, or material support (i.e., reporting or organizing data, constructing databases).

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Correspondence to Jianli Hu.

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Wen, L., Yang, S., Li, P. et al. iASPP-Mediated ROS Inhibition Drives 5-Fu Resistance Dependent on Nrf2 Antioxidative Signaling Pathway in Gastric Adenocarcinoma. Dig Dis Sci 65, 2873–2883 (2020). https://doi.org/10.1007/s10620-019-06022-6

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