Cargando…
Inhibition of TRPM7 suppresses cell proliferation of colon adenocarcinoma in vitro and induces hypomagnesemia in vivo without affecting azoxymethane-induced early colon cancer in mice
BACKGROUND: Magnesium (Mg(2+)) is an essential cation implicated in carcinogenesis, solid tumor progression and metastatic potential. The Transient Receptor Potential Melastatin Member 7 (TRPM7) is a divalent ion channel involved in cellular and systemic Mg(2+) homeostasis. Abnormal expression of TR...
Autores principales: | , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2017
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5558780/ https://www.ncbi.nlm.nih.gov/pubmed/28810912 http://dx.doi.org/10.1186/s12964-017-0187-9 |
_version_ | 1783257449263792128 |
---|---|
author | Huang, Junhao Furuya, Hideki Faouzi, Malika Zhang, Zheng Monteilh-Zoller, Mahealani Kelly Galbraith Kawabata, F. Horgen, David Kawamori, Toshihiko Penner, Reinhold Fleig, Andrea |
author_facet | Huang, Junhao Furuya, Hideki Faouzi, Malika Zhang, Zheng Monteilh-Zoller, Mahealani Kelly Galbraith Kawabata, F. Horgen, David Kawamori, Toshihiko Penner, Reinhold Fleig, Andrea |
author_sort | Huang, Junhao |
collection | PubMed |
description | BACKGROUND: Magnesium (Mg(2+)) is an essential cation implicated in carcinogenesis, solid tumor progression and metastatic potential. The Transient Receptor Potential Melastatin Member 7 (TRPM7) is a divalent ion channel involved in cellular and systemic Mg(2+) homeostasis. Abnormal expression of TRPM7 is found in numerous cancers, including colon, implicating TRPM7 in this process. METHODS: To establish a possible link between systemic magnesium (Mg(2+)) status, the Mg(2+) conducting channel TRPM7 in colon epithelial cells, and colon carcinogenesis, in vitro whole-cell patch clamp electrophysiology, qPCR, and pharmacological tools were used probing human colorectal adenocarcinoma HT-29 as well as normal primary mouse colon epithelial cells. This was extended to and combined with aberrant crypt foci development in an azoxymethane-induced colorectal cancer mouse model under hypomagnesemia induced by diet or pharmacologic intervention. RESULTS: We find that TRPM7 drives colon cancer cell proliferation in human HT-29 and expresses in normal primary mouse colon epithelia. This is linked to TRPM7’s dominant role as Mg(2+) transporter, since high extracellular Mg(2+) supplementation cannot rescue inhibition of cell proliferation caused by suppressing TRPM7 either genetically or pharmacologically. In vivo experiments in mice provide evidence that the specific TRPM7 inhibitor waixenicin A, given as a single bolus injection, induces transient hypomagnesemia and increases intestinal absorption of calcium. Repeated injections of waixenicin A over 3 weeks cause hypomagnesemia via insufficient Mg(2+) absorption by the colon. However, neither waixenicin A, nor a diet low in Mg(2+), affect aberrant crypt foci development in an azoxymethane-induced colorectal cancer mouse model. CONCLUSION: Early stage colon cancer proceeds independent of systemic Mg(2+) status and TRPM7, and waixenicin A is a useful pharmacological tool to study of TRPM7 in vitro and in vivo. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12964-017-0187-9) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-5558780 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-55587802017-08-18 Inhibition of TRPM7 suppresses cell proliferation of colon adenocarcinoma in vitro and induces hypomagnesemia in vivo without affecting azoxymethane-induced early colon cancer in mice Huang, Junhao Furuya, Hideki Faouzi, Malika Zhang, Zheng Monteilh-Zoller, Mahealani Kelly Galbraith Kawabata, F. Horgen, David Kawamori, Toshihiko Penner, Reinhold Fleig, Andrea Cell Commun Signal Research BACKGROUND: Magnesium (Mg(2+)) is an essential cation implicated in carcinogenesis, solid tumor progression and metastatic potential. The Transient Receptor Potential Melastatin Member 7 (TRPM7) is a divalent ion channel involved in cellular and systemic Mg(2+) homeostasis. Abnormal expression of TRPM7 is found in numerous cancers, including colon, implicating TRPM7 in this process. METHODS: To establish a possible link between systemic magnesium (Mg(2+)) status, the Mg(2+) conducting channel TRPM7 in colon epithelial cells, and colon carcinogenesis, in vitro whole-cell patch clamp electrophysiology, qPCR, and pharmacological tools were used probing human colorectal adenocarcinoma HT-29 as well as normal primary mouse colon epithelial cells. This was extended to and combined with aberrant crypt foci development in an azoxymethane-induced colorectal cancer mouse model under hypomagnesemia induced by diet or pharmacologic intervention. RESULTS: We find that TRPM7 drives colon cancer cell proliferation in human HT-29 and expresses in normal primary mouse colon epithelia. This is linked to TRPM7’s dominant role as Mg(2+) transporter, since high extracellular Mg(2+) supplementation cannot rescue inhibition of cell proliferation caused by suppressing TRPM7 either genetically or pharmacologically. In vivo experiments in mice provide evidence that the specific TRPM7 inhibitor waixenicin A, given as a single bolus injection, induces transient hypomagnesemia and increases intestinal absorption of calcium. Repeated injections of waixenicin A over 3 weeks cause hypomagnesemia via insufficient Mg(2+) absorption by the colon. However, neither waixenicin A, nor a diet low in Mg(2+), affect aberrant crypt foci development in an azoxymethane-induced colorectal cancer mouse model. CONCLUSION: Early stage colon cancer proceeds independent of systemic Mg(2+) status and TRPM7, and waixenicin A is a useful pharmacological tool to study of TRPM7 in vitro and in vivo. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12964-017-0187-9) contains supplementary material, which is available to authorized users. BioMed Central 2017-08-15 /pmc/articles/PMC5558780/ /pubmed/28810912 http://dx.doi.org/10.1186/s12964-017-0187-9 Text en © The Author(s). 2017 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Huang, Junhao Furuya, Hideki Faouzi, Malika Zhang, Zheng Monteilh-Zoller, Mahealani Kelly Galbraith Kawabata, F. Horgen, David Kawamori, Toshihiko Penner, Reinhold Fleig, Andrea Inhibition of TRPM7 suppresses cell proliferation of colon adenocarcinoma in vitro and induces hypomagnesemia in vivo without affecting azoxymethane-induced early colon cancer in mice |
title | Inhibition of TRPM7 suppresses cell proliferation of colon adenocarcinoma in vitro and induces hypomagnesemia in vivo without affecting azoxymethane-induced early colon cancer in mice |
title_full | Inhibition of TRPM7 suppresses cell proliferation of colon adenocarcinoma in vitro and induces hypomagnesemia in vivo without affecting azoxymethane-induced early colon cancer in mice |
title_fullStr | Inhibition of TRPM7 suppresses cell proliferation of colon adenocarcinoma in vitro and induces hypomagnesemia in vivo without affecting azoxymethane-induced early colon cancer in mice |
title_full_unstemmed | Inhibition of TRPM7 suppresses cell proliferation of colon adenocarcinoma in vitro and induces hypomagnesemia in vivo without affecting azoxymethane-induced early colon cancer in mice |
title_short | Inhibition of TRPM7 suppresses cell proliferation of colon adenocarcinoma in vitro and induces hypomagnesemia in vivo without affecting azoxymethane-induced early colon cancer in mice |
title_sort | inhibition of trpm7 suppresses cell proliferation of colon adenocarcinoma in vitro and induces hypomagnesemia in vivo without affecting azoxymethane-induced early colon cancer in mice |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5558780/ https://www.ncbi.nlm.nih.gov/pubmed/28810912 http://dx.doi.org/10.1186/s12964-017-0187-9 |
work_keys_str_mv | AT huangjunhao inhibitionoftrpm7suppressescellproliferationofcolonadenocarcinomainvitroandinduceshypomagnesemiainvivowithoutaffectingazoxymethaneinducedearlycoloncancerinmice AT furuyahideki inhibitionoftrpm7suppressescellproliferationofcolonadenocarcinomainvitroandinduceshypomagnesemiainvivowithoutaffectingazoxymethaneinducedearlycoloncancerinmice AT faouzimalika inhibitionoftrpm7suppressescellproliferationofcolonadenocarcinomainvitroandinduceshypomagnesemiainvivowithoutaffectingazoxymethaneinducedearlycoloncancerinmice AT zhangzheng inhibitionoftrpm7suppressescellproliferationofcolonadenocarcinomainvitroandinduceshypomagnesemiainvivowithoutaffectingazoxymethaneinducedearlycoloncancerinmice AT monteilhzollermahealani inhibitionoftrpm7suppressescellproliferationofcolonadenocarcinomainvitroandinduceshypomagnesemiainvivowithoutaffectingazoxymethaneinducedearlycoloncancerinmice AT kellygalbraithkawabataf inhibitionoftrpm7suppressescellproliferationofcolonadenocarcinomainvitroandinduceshypomagnesemiainvivowithoutaffectingazoxymethaneinducedearlycoloncancerinmice AT horgendavid inhibitionoftrpm7suppressescellproliferationofcolonadenocarcinomainvitroandinduceshypomagnesemiainvivowithoutaffectingazoxymethaneinducedearlycoloncancerinmice AT kawamoritoshihiko inhibitionoftrpm7suppressescellproliferationofcolonadenocarcinomainvitroandinduceshypomagnesemiainvivowithoutaffectingazoxymethaneinducedearlycoloncancerinmice AT pennerreinhold inhibitionoftrpm7suppressescellproliferationofcolonadenocarcinomainvitroandinduceshypomagnesemiainvivowithoutaffectingazoxymethaneinducedearlycoloncancerinmice AT fleigandrea inhibitionoftrpm7suppressescellproliferationofcolonadenocarcinomainvitroandinduceshypomagnesemiainvivowithoutaffectingazoxymethaneinducedearlycoloncancerinmice |