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TRPM5 mediates acidic extracellular pH signaling and TRPM5 inhibition reduces spontaneous metastasis in mouse B16-BL6 melanoma cells

Extracellular acidity is a hallmark of solid tumors and is associated with metastasis in the tumor microenvironment. Acidic extracellular pH (pH(e)) has been found to increase intracellular Ca(2+) and matrix metalloproteinase-9 (MMP-9) expression by activating NF-κB in the mouse B16 melanoma model....

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Autores principales: Maeda, Toyonobu, Suzuki, Atsuko, Koga, Kaori, Miyamoto, Chihiro, Maehata, Yojiro, Ozawa, Shigeyuki, Hata, Ryu-Ichiro, Nagashima, Yoji, Nabeshima, Kazuki, Miyazaki, Kaoru, Kato, Yasumasa
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5667964/
https://www.ncbi.nlm.nih.gov/pubmed/29108231
http://dx.doi.org/10.18632/oncotarget.20826
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author Maeda, Toyonobu
Suzuki, Atsuko
Koga, Kaori
Miyamoto, Chihiro
Maehata, Yojiro
Ozawa, Shigeyuki
Hata, Ryu-Ichiro
Nagashima, Yoji
Nabeshima, Kazuki
Miyazaki, Kaoru
Kato, Yasumasa
author_facet Maeda, Toyonobu
Suzuki, Atsuko
Koga, Kaori
Miyamoto, Chihiro
Maehata, Yojiro
Ozawa, Shigeyuki
Hata, Ryu-Ichiro
Nagashima, Yoji
Nabeshima, Kazuki
Miyazaki, Kaoru
Kato, Yasumasa
author_sort Maeda, Toyonobu
collection PubMed
description Extracellular acidity is a hallmark of solid tumors and is associated with metastasis in the tumor microenvironment. Acidic extracellular pH (pH(e)) has been found to increase intracellular Ca(2+) and matrix metalloproteinase-9 (MMP-9) expression by activating NF-κB in the mouse B16 melanoma model. The present study assessed whether TRPM5, an intracellular Ca(2+)-dependent monovalent cation channel, is associated with acidic pH(e) signaling and induction of MMP-9 expression in this mouse melanoma model. Treatment of B16 cells with Trpm5 siRNA reduced acidic pH(e)-induced MMP-9 expression. Enforced expression of Trpm5 increased the rate of acidic pH(e)-induced MMP-9 expression, as well as increasing experimental lung metastasis. This genetic manipulation did not alter the pH(e) critical for MMP-9 induction but simply amplified the percentage of inducible MMP-9 at each pH(e). Treatment of tumor bearing mice with triphenylphosphine oxide (TPPO), an inhibitor of TRPM5, significantly reduced spontaneous lung metastasis. In silico analysis of clinical samples showed that high TRPM5 mRNA expression correlated with poor overall survival rate in patients with melanoma and gastric cancer but not in patients with cancers of the ovary, lung, breast, and rectum. These results showed that TRPM5 amplifies acidic pH(e) signaling and may be a promising target for preventing metastasis of some types of tumor.
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spelling pubmed-56679642017-11-04 TRPM5 mediates acidic extracellular pH signaling and TRPM5 inhibition reduces spontaneous metastasis in mouse B16-BL6 melanoma cells Maeda, Toyonobu Suzuki, Atsuko Koga, Kaori Miyamoto, Chihiro Maehata, Yojiro Ozawa, Shigeyuki Hata, Ryu-Ichiro Nagashima, Yoji Nabeshima, Kazuki Miyazaki, Kaoru Kato, Yasumasa Oncotarget Research Paper Extracellular acidity is a hallmark of solid tumors and is associated with metastasis in the tumor microenvironment. Acidic extracellular pH (pH(e)) has been found to increase intracellular Ca(2+) and matrix metalloproteinase-9 (MMP-9) expression by activating NF-κB in the mouse B16 melanoma model. The present study assessed whether TRPM5, an intracellular Ca(2+)-dependent monovalent cation channel, is associated with acidic pH(e) signaling and induction of MMP-9 expression in this mouse melanoma model. Treatment of B16 cells with Trpm5 siRNA reduced acidic pH(e)-induced MMP-9 expression. Enforced expression of Trpm5 increased the rate of acidic pH(e)-induced MMP-9 expression, as well as increasing experimental lung metastasis. This genetic manipulation did not alter the pH(e) critical for MMP-9 induction but simply amplified the percentage of inducible MMP-9 at each pH(e). Treatment of tumor bearing mice with triphenylphosphine oxide (TPPO), an inhibitor of TRPM5, significantly reduced spontaneous lung metastasis. In silico analysis of clinical samples showed that high TRPM5 mRNA expression correlated with poor overall survival rate in patients with melanoma and gastric cancer but not in patients with cancers of the ovary, lung, breast, and rectum. These results showed that TRPM5 amplifies acidic pH(e) signaling and may be a promising target for preventing metastasis of some types of tumor. Impact Journals LLC 2017-09-11 /pmc/articles/PMC5667964/ /pubmed/29108231 http://dx.doi.org/10.18632/oncotarget.20826 Text en Copyright: © 2017 Maeda et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Maeda, Toyonobu
Suzuki, Atsuko
Koga, Kaori
Miyamoto, Chihiro
Maehata, Yojiro
Ozawa, Shigeyuki
Hata, Ryu-Ichiro
Nagashima, Yoji
Nabeshima, Kazuki
Miyazaki, Kaoru
Kato, Yasumasa
TRPM5 mediates acidic extracellular pH signaling and TRPM5 inhibition reduces spontaneous metastasis in mouse B16-BL6 melanoma cells
title TRPM5 mediates acidic extracellular pH signaling and TRPM5 inhibition reduces spontaneous metastasis in mouse B16-BL6 melanoma cells
title_full TRPM5 mediates acidic extracellular pH signaling and TRPM5 inhibition reduces spontaneous metastasis in mouse B16-BL6 melanoma cells
title_fullStr TRPM5 mediates acidic extracellular pH signaling and TRPM5 inhibition reduces spontaneous metastasis in mouse B16-BL6 melanoma cells
title_full_unstemmed TRPM5 mediates acidic extracellular pH signaling and TRPM5 inhibition reduces spontaneous metastasis in mouse B16-BL6 melanoma cells
title_short TRPM5 mediates acidic extracellular pH signaling and TRPM5 inhibition reduces spontaneous metastasis in mouse B16-BL6 melanoma cells
title_sort trpm5 mediates acidic extracellular ph signaling and trpm5 inhibition reduces spontaneous metastasis in mouse b16-bl6 melanoma cells
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5667964/
https://www.ncbi.nlm.nih.gov/pubmed/29108231
http://dx.doi.org/10.18632/oncotarget.20826
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