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Lactate secreted via MCT4 from bone‑colonizing breast cancer excites sensory neurons via GPR81

  • Authors:
    • Tatsuo Okui
    • Masahiro Hiasa
    • Kazuaki Hasegawa
    • Tomoya Nakamura
    • Kisho Ono
    • Soichiro Ibaragi
    • Takahiro Kanno
    • Akira Sasaki
    • Toshiyuki Yoneda
  • View Affiliations / Copyright

    Affiliations: Department of Oral and Maxillofacial Surgery, Shimane University Faculty of Medicine, Izumo, Shimane 693‑8501, Japan, Department of Medicine, Hematology Oncology, Indiana University School of Medicine and The Roudebush Veterans Administration, Indianapolis, IN 46202, USA, Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2‑5‑1 Shikata‑cho, Okayama, Okayama 700‑8525, Japan
    Copyright: © Okui et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 39
    |
    Published online on: February 8, 2023
       https://doi.org/10.3892/ijo.2023.5487
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Abstract

Breast cancer (BC) bone metastasis causes bone pain (BP), which detrimentally damages the quality of life and outcome of patients with BC. However, the mechanism of BC‑BP is poorly understood, and effective treatments are limited. The present study demonstrated a novel mechanism of BC‑BP using a mouse model of bone pain, in which mouse (EO771) and human (MDA‑MB‑231) BC cells were injected in the bone marrow cavity of tibiae. Western blot analysis using sensory nerves, in vivo assessment of cancer pain and in vitro calcium flux analysis were performed. These mice developed progressive BC‑BP in tibiae in conjunction with an upregulation of phosphorylated pERK1/2 and cAMP‑response element‑binding protein (pCREB), which are molecular indicators of neuron excitation, in the dorsal root ganglia (DRG) of sensory nerves. Importantly, mice injected with BC cells, in which the expression of the lactic acid transporter monocarboxylate transporter 4 (MCT4) was silenced, exhibited decreased BC‑BP with downregulated expression of pERK1/2 and pCREB in the DRG and reduced circulating levels of lactate compared with mice injected with parental BC cells. Further, silencing of the cell‑surface orphan receptor for lactate, G protein‑coupled receptor 81 (GPR81), in the F11 sensory neuron cells decreased lactate‑promoted upregulation of pERK1/2 and Ca2+ influx, suggesting that the sensory neuron excitation was inhibited. These results suggested that lactate released from BC cells via MCT4 induced BC‑BP through the activation of GPR81 of sensory neurons. In conclusion, the activation of GPR81 of sensory neurons by lactate released via MCT4 from BC was demonstrated to contribute to the induction of BC‑BP, and disruption of the interactions among lactate, MCT4 and GPR81 may be a novel approach to control BC‑BP.
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Copy and paste a formatted citation
Spandidos Publications style
Okui T, Hiasa M, Hasegawa K, Nakamura T, Ono K, Ibaragi S, Kanno T, Sasaki A and Yoneda T: Lactate secreted via MCT4 from bone‑colonizing breast cancer excites sensory neurons via GPR81. Int J Oncol 62: 39, 2023.
APA
Okui, T., Hiasa, M., Hasegawa, K., Nakamura, T., Ono, K., Ibaragi, S. ... Yoneda, T. (2023). Lactate secreted via MCT4 from bone‑colonizing breast cancer excites sensory neurons via GPR81. International Journal of Oncology, 62, 39. https://doi.org/10.3892/ijo.2023.5487
MLA
Okui, T., Hiasa, M., Hasegawa, K., Nakamura, T., Ono, K., Ibaragi, S., Kanno, T., Sasaki, A., Yoneda, T."Lactate secreted via MCT4 from bone‑colonizing breast cancer excites sensory neurons via GPR81". International Journal of Oncology 62.3 (2023): 39.
Chicago
Okui, T., Hiasa, M., Hasegawa, K., Nakamura, T., Ono, K., Ibaragi, S., Kanno, T., Sasaki, A., Yoneda, T."Lactate secreted via MCT4 from bone‑colonizing breast cancer excites sensory neurons via GPR81". International Journal of Oncology 62, no. 3 (2023): 39. https://doi.org/10.3892/ijo.2023.5487
Copy and paste a formatted citation
x
Spandidos Publications style
Okui T, Hiasa M, Hasegawa K, Nakamura T, Ono K, Ibaragi S, Kanno T, Sasaki A and Yoneda T: Lactate secreted via MCT4 from bone‑colonizing breast cancer excites sensory neurons via GPR81. Int J Oncol 62: 39, 2023.
APA
Okui, T., Hiasa, M., Hasegawa, K., Nakamura, T., Ono, K., Ibaragi, S. ... Yoneda, T. (2023). Lactate secreted via MCT4 from bone‑colonizing breast cancer excites sensory neurons via GPR81. International Journal of Oncology, 62, 39. https://doi.org/10.3892/ijo.2023.5487
MLA
Okui, T., Hiasa, M., Hasegawa, K., Nakamura, T., Ono, K., Ibaragi, S., Kanno, T., Sasaki, A., Yoneda, T."Lactate secreted via MCT4 from bone‑colonizing breast cancer excites sensory neurons via GPR81". International Journal of Oncology 62.3 (2023): 39.
Chicago
Okui, T., Hiasa, M., Hasegawa, K., Nakamura, T., Ono, K., Ibaragi, S., Kanno, T., Sasaki, A., Yoneda, T."Lactate secreted via MCT4 from bone‑colonizing breast cancer excites sensory neurons via GPR81". International Journal of Oncology 62, no. 3 (2023): 39. https://doi.org/10.3892/ijo.2023.5487
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