Research Papers:

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

Toyonobu Maeda, Atsuko Suzuki, Kaori Koga, Chihiro Miyamoto, Yojiro Maehata, Shigeyuki Ozawa, Ryu-Ichiro Hata, Yoji Nagashima, Kazuki Nabeshima, Kaoru Miyazaki and Yasumasa Kato _

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Oncotarget. 2017; 8:78312-78326. https://doi.org/10.18632/oncotarget.20826

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Toyonobu Maeda1,*, Atsuko Suzuki1,*, Kaori Koga2, Chihiro Miyamoto3, Yojiro Maehata3, Shigeyuki Ozawa4, Ryu-Ichiro Hata4,5, Yoji Nagashima6, Kazuki Nabeshima2, Kaoru Miyazaki7 and Yasumasa Kato1

1Department of Oral Function and Molecular Biology, Ohu University School of Dentistry, Koriyama 963-8611, Japan

2Department of Pathology, Fukuoka University School of Medicine and Hospital, Fukuoka 814-0180, Japan

3Department of Oral Science, Kanagawa Dental University Graduate School of Dentistry, Yokosuka 238-8580, Japan

4Department of Dentomaxillofacial Diagnosis and Treatment, Kanagawa Dental University Graduate School of Dentistry, Yokosuka 238-8580, Japan

5Oral Health Science Research Center, Kanagawa Dental University Graduate School of Dentistry, Yokosuka 238-8580, Japan

6Department of Surgical Pathology, Tokyo Women’s Medical University Hospital, Tokyo 162-8666, Japan

7Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, Yokohama 241-8515, Japan

*These authors contributed equally to this work

Correspondence to:

Yasumasa Kato, email: [email protected]

Keywords: MMP-9, acidic extracellular pH, TRPM5, melanoma, metastasis

Received: April 28, 2017     Accepted: August 27, 2017     Published: September 11, 2017


Extracellular acidity is a hallmark of solid tumors and is associated with metastasis in the tumor microenvironment. Acidic extracellular pH (pHe) has been found to increase intracellular Ca2+ 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 Ca2+-dependent monovalent cation channel, is associated with acidic pHe signaling and induction of MMP-9 expression in this mouse melanoma model. Treatment of B16 cells with Trpm5 siRNA reduced acidic pHe-induced MMP-9 expression. Enforced expression of Trpm5 increased the rate of acidic pHe-induced MMP-9 expression, as well as increasing experimental lung metastasis. This genetic manipulation did not alter the pHe critical for MMP-9 induction but simply amplified the percentage of inducible MMP-9 at each pHe. 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 pHe signaling and may be a promising target for preventing metastasis of some types of tumor.

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