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Six-transmembrane epithelial antigen of the prostate 1 protects against increased oxidative stress via a nuclear erythroid 2-related factor pathway in colorectal cancer

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Abstract

The over-expression of six-transmembrane epithelial antigen of the prostate 1 (STEAP1) underlies the pathogenesis of a large subset of human cancers. Expressed on the cancer cell surface, STEAP1 is an attractive target for antibody-based therapy or immunotherapy. However, its role in modulating the pathophysiology of colorectal cancer (CRC) remains relatively unexplored. In this study, we first demonstrated that the STEAP1 transcript level was significantly higher in CRC tissues than in normal colonic tissues. Of note, STEAP1 expression negatively correlated with overall survival as determined from a publicly accessible gene expression profile data set. A loss-of-function approach in cultured CRC cell lines revealed that STEAP1 silencing suppressed cell growth and increased reactive oxygen species (ROS) production, followed by apoptosis, through an intrinsic pathway. Mechanistically, the inhibition of STEAP1 was associated with decreased expression of antioxidant molecules regulated by the transcription factor, nuclear erythroid 2-related factor (NRF2), in CRC cells. Taken together, we identified high STEAP1 transcript levels leading to reduced ROS production that prevented apoptosis via the NRF2 pathway in CRC cells as a pathological mechanism in CRC. This study highlights the STEAP1–NRF2 axis as a therapeutic target for CRC and its manipulation as a novel strategy to conquer CRC.

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Acknowledgements

We thank Yukie Nakamura for her excellent technical assistance.

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Author notes

  1. These authors contributed equally: Hajime Nakamura, Kohichi Takada

Authors and Affiliations

  1. Department of Medical Oncology, Sapporo Medical University School of Medicine, Hokkaidō, Japan

    Hajime Nakamura, Kohichi Takada, Yohei Arihara, Naotaka Hayasaka, Kazuyuki Murase, Koji Miyanishi & Junji Kato

  2. Department of Hematology, Sapporo Medical University School of Medicine, Hokkaidō, Japan

    Kohichi Takada, Kazuyuki Murase, Satoshi Iyama & Masayoshi Kobune

Authors
  1. Hajime Nakamura
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  2. Kohichi Takada
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  3. Yohei Arihara
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  4. Naotaka Hayasaka
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  5. Kazuyuki Murase
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  6. Satoshi Iyama
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Correspondence to Koji Miyanishi.

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Nakamura, H., Takada, K., Arihara, Y. et al. Six-transmembrane epithelial antigen of the prostate 1 protects against increased oxidative stress via a nuclear erythroid 2-related factor pathway in colorectal cancer. Cancer Gene Ther 26, 313–322 (2019). https://doi.org/10.1038/s41417-018-0056-8

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