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Cryptotanshinone, a novel PDK 4 inhibitor, suppresses bladder cancer cell invasiveness via the mTOR/β‑catenin/N‑cadherin axis

  • Authors:
    • Chul Jang Kim
    • Tokio Terado
    • Yukihiro Tambe
    • Ken-Ichi Mukaisho
    • Susumu Kageyama
    • Akihiro Kawauchi
    • Hirokazu Inoue
  • View Affiliations / Copyright

    Affiliations: Department of Urology, Kohka Public Hospital, Minakuchi‑cho, Kohka, Shiga 528‑0074, Japan, Department of Stem Cell Biology and Regenerative Medicine, Shiga University of Medical Science, Setatsukinowa‑cho, Otsu, Shiga 520‑2192, Japan, Division of Microbiology and Infectious Diseases, Shiga University of Medical Science, Setatsukinowa‑cho, Otsu, Shiga 520‑2192, Japan, Division of Human Pathology, Shiga University of Medical Science, Setatsukinowa‑cho, Otsu, Shiga 520‑2192, Japan, Department of Urology, Shiga University of Medical Science, Setatsukinowa‑cho, Otsu, Shiga 520‑2192, Japan
    Copyright: © Kim et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY 4.0].
  • Article Number: 40
    |
    Published online on: May 13, 2021
       https://doi.org/10.3892/ijo.2021.5220
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Abstract

The phosphorylation of pyruvate dehydrogenase (PDH) by pyruvate dehydrogenase kinase (PDK) 4 inhibits its ability to induce a glycolytic shift. PDK4 expression is upregulated in various types of human cancer. Because PDK4 regulation is critical for metabolic changes in cancer cells, it is an attractive target for cancer therapy given its ability to shift glucose metabolism. It was previously shown that a novel PDK4 inhibitor, cryptotanshinone (CPT), suppressed the three‑dimensional (3D)‑spheroid formation of pancreatic and colorectal cancer cells. In the present study, the effects of CPT on the invasiveness of bladder cancer cells were investigated. CPT significantly suppressed the invasiveness and 3D‑spheroid formation of T24 and J82 bladder cancer cells. CPT also suppressed the phosphorylation of PDH and β‑catenin, as well as the expression of N‑cadherin, which are all critical for inducing epithelial‑mesenchymal transition (EMT). The knockdown of β‑catenin or PDK4 using specific small interfering RNAs suppressed N‑cadherin expression and invasiveness in T24 cells. An mTOR inhibitor also suppressed the phosphorylation of β‑catenin and N‑cadherin expression. Furthermore, CPT injection significantly suppressed pancreatic tumor growth and peritoneal dissemination of highly metastatic SUIT‑2 pancreatic cancer cells in a mouse orthotopic pancreatic cancer model, without evident toxicity. Moreover, immunohistochemistry analyses demonstrated decreased β‑catenin expression in CPT‑treated pancreatic tumors compared with control tumors. Taken together, these results indicate that CPT reduced the invasiveness and metastasis of bladder cancer cells by suppressing EMT via the mTOR/β‑catenin/N‑cadherin pathway.
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Copy and paste a formatted citation
Spandidos Publications style
Kim CJ, Terado T, Tambe Y, Mukaisho K, Kageyama S, Kawauchi A and Inoue H: Cryptotanshinone, a novel PDK 4 inhibitor, suppresses bladder cancer cell invasiveness via the mTOR/β‑catenin/N‑cadherin axis. Int J Oncol 59: 40, 2021.
APA
Kim, C.J., Terado, T., Tambe, Y., Mukaisho, K., Kageyama, S., Kawauchi, A., & Inoue, H. (2021). Cryptotanshinone, a novel PDK 4 inhibitor, suppresses bladder cancer cell invasiveness via the mTOR/β‑catenin/N‑cadherin axis. International Journal of Oncology, 59, 40. https://doi.org/10.3892/ijo.2021.5220
MLA
Kim, C. J., Terado, T., Tambe, Y., Mukaisho, K., Kageyama, S., Kawauchi, A., Inoue, H."Cryptotanshinone, a novel PDK 4 inhibitor, suppresses bladder cancer cell invasiveness via the mTOR/β‑catenin/N‑cadherin axis". International Journal of Oncology 59.1 (2021): 40.
Chicago
Kim, C. J., Terado, T., Tambe, Y., Mukaisho, K., Kageyama, S., Kawauchi, A., Inoue, H."Cryptotanshinone, a novel PDK 4 inhibitor, suppresses bladder cancer cell invasiveness via the mTOR/β‑catenin/N‑cadherin axis". International Journal of Oncology 59, no. 1 (2021): 40. https://doi.org/10.3892/ijo.2021.5220
Copy and paste a formatted citation
x
Spandidos Publications style
Kim CJ, Terado T, Tambe Y, Mukaisho K, Kageyama S, Kawauchi A and Inoue H: Cryptotanshinone, a novel PDK 4 inhibitor, suppresses bladder cancer cell invasiveness via the mTOR/β‑catenin/N‑cadherin axis. Int J Oncol 59: 40, 2021.
APA
Kim, C.J., Terado, T., Tambe, Y., Mukaisho, K., Kageyama, S., Kawauchi, A., & Inoue, H. (2021). Cryptotanshinone, a novel PDK 4 inhibitor, suppresses bladder cancer cell invasiveness via the mTOR/β‑catenin/N‑cadherin axis. International Journal of Oncology, 59, 40. https://doi.org/10.3892/ijo.2021.5220
MLA
Kim, C. J., Terado, T., Tambe, Y., Mukaisho, K., Kageyama, S., Kawauchi, A., Inoue, H."Cryptotanshinone, a novel PDK 4 inhibitor, suppresses bladder cancer cell invasiveness via the mTOR/β‑catenin/N‑cadherin axis". International Journal of Oncology 59.1 (2021): 40.
Chicago
Kim, C. J., Terado, T., Tambe, Y., Mukaisho, K., Kageyama, S., Kawauchi, A., Inoue, H."Cryptotanshinone, a novel PDK 4 inhibitor, suppresses bladder cancer cell invasiveness via the mTOR/β‑catenin/N‑cadherin axis". International Journal of Oncology 59, no. 1 (2021): 40. https://doi.org/10.3892/ijo.2021.5220
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