Transient receptor potential melastatin 6 and transient receptor potential melastatin 6/7 antagonists suppress colon adenocarcinoma HT-29 cells

doi:10.4251/wjgo.v17.i12.110736

Advanced Search

BPG is committed to discovery and dissemination of knowledge

Home / Archive / Volume 17, Issue 12

This Article

Academic Content and Language Evaluation of This Article

CrossCheck and Google Search of This Article

Academic Rules and Norms of This Article

Citation of this article

Corresponding Author of This Article

Research Domain of This Article

Article-Type of This Article

Open-Access Policy of This Article

Times Cited Counts in Google of This Article

Number of Hits and Downloads for This Article

Total Article Views (123)

All Articles published online

The chart showing PDF series, HTML series, Figures (1-7) series, Tables (1-3) series.

Item

Count

PDF

HTML

Figures (1-7)

Tables (1-3)

Sum=81

Publishing Process of This Article

The chart showing Browse series, Download series.

Item

Count

Browse

Download

Sum=29

Dec 15, 2025 (publication date) through Dec 17, 2025

Times Cited of This Article

Times Cited (0)

Journal Information of This Article

Publication Name

World Journal of Gastrointestinal Oncology

ISSN

1948-5204

Publisher of This Article

Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA

Basic Study

World J Gastrointest Oncol. Dec 15, 2025; 17(12): 110736
Published online Dec 15, 2025. doi: 10.4251/wjgo.v17.i12.110736

Transient receptor potential melastatin 6 and transient receptor potential melastatin 6/7 antagonists suppress colon adenocarcinoma HT-29 cells

Nattida Kampuang, Siriporn Chamniansawat, Pawin Pongkorpsakol, Supisara Treveeravoot, Narongrit Thongon

Nattida Kampuang, Siriporn Chamniansawat, Narongrit Thongon, Department of Medical Sciences, Faculty of Allied Health Sciences, Burapha University, Muang 20131, Chonburi, Thailand

Pawin Pongkorpsakol, Supisara Treveeravoot, Princess Srisavangavadhana Faculty of Medicine, Chulabhorn Royal Academy, Lak Si 10210, Bangkok, Thailand

Author contributions: Kampuang N and Thongon N designed experiments, analyzed and interpreted the results; Chamniansawat S, Pongkorpsakol P, and Thongon N edited the manuscript; Thongon N wrote the manuscript; all authors performed the experiments and approved the final version to publish.

Supported by Burapha University, Thailand Science Research and Innovation, and National Science Research and Innovation Fund, No. 53/2567.

Institutional review board statement: All experimental protocols in this study were carried out exclusively with cell lines, and therefore no experiments involving human participants or animal subjects were required.

Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.

Data sharing statement: The data could be downloaded from the public databases, and no additional data are available.

Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/

Corresponding author: Narongrit Thongon, PhD, Associate Professor, Department of Medical Sciences, Faculty of Allied Health Sciences, Burapha University, 169 Long-Hard Bangsaen Road, Saensook, Muang 20131, Chonburi, Thailand. narongritt@buu.ac.th

Received: June 16, 2025
Revised: July 8, 2025
Accepted: October 17, 2025
Published online: December 15, 2025
Processing time: 181 Days and 6.3 Hours

Abstract

BACKGROUND

Magnesium (Mg²⁺) plays a fundamental role in numerous cellular processes, including enzymatic reactions, DNA replication, oxidative stress response, and cytoskeletal dynamics. In fact, dysregulation of Mg²⁺ homeostasis has been increasingly associated with the development and progression of cancer, particularly colorectal cancer (CRC). Transient receptor potential melastatin (TRPM) channels, especially TRPM6 and TRPM7, are essential regulators of epithelial Mg²⁺ influx. While TRPM7 promotes CRC progression, the role of TRPM6 and TRPM6/7 channels remains unclear.

AIM

To investigate the role of membrane-localized TRPM6 and TRPM6/7 channels in Mg²⁺ influx, spheroid (SP) formation, stemness, and migration.

METHODS

We used parental and SP-derived HT-29 cells at comparable passages as in vitro models. Mass spectrometry confirmed full-length sequences, phosphorylation, and methionine oxidation of TRPM6 and TRPM7. Mg²⁺ influx, total and free Mg²⁺ levels were measured by fluorescence imaging and biochemical assays. TRPM6 / TRPM7 expression and markers were analyzed by western blot. Functional assays, including secondary SP formation and wound healing, assessed stemness and migration. Cells were treated with Mg²⁺ transport inhibitors: Co(III)hexamine, 2-aminoethyl diphenylborinate (TRPM6/7 blocker), and Mesendogen (TRPM6 inhibitor).

RESULTS

The expression of membrane-bound TRPM6, TRPM7, and TRPM6/7 was significantly higher in SP cells than in parental cells. Mass spectrometric analysis confirmed the presence of full-length TRPM6 and TRPM7 with increased phosphorylation and oxidation in SP cells. Enhanced Mg²⁺ influx and total intracellular Mg²⁺ levels were observed in SP cells. Free ionized intracellular Mg²⁺ levels remained comparable across all experimental groups. Pharmacological inhibition of TRPM6 and TRPM6/7 significantly reduced Mg²⁺ influx, decreased total Mg²⁺ content, compromised CRC SP stability, abolished cancer stem-like properties, impaired cell migration, and downregulated pro-tumorigenic markers, including Nanog, cyclooxygenase-2, and matrix metalloproteinase-9.

CONCLUSION

Membrane-localized TRPM6 and TRPM6/7 channels regulate Mg²⁺ influx and promote CRC stemness, SP stability, and migration, highlighting their potential as therapeutic targets to inhibit CRC progression and metastasis.

Keywords: Cancer stem cells; Cellular Mg²⁺ content; Colorectal cancer; Transient receptor potential melastatin 6/7; Transient receptor potential melastatin 6

Core Tip: This study demonstrated that colorectal cancer (CRC) spheroids (SPs) exhibited significantly increased membrane expression and phosphorylation of transient receptor potential melastatin (TRPM) 6 and TRPM6/7 channels, which enhanced magnesium (Mg²⁺) influx and promoted intracellular Mg²⁺ accumulation. However, selective TRPM6 and TRPM6/7 inhibitors markedly suppressed Mg²⁺ influx, SP formation, cell viability, and migration and impaired cancer stem-like properties. These findings highlight the critical role of TRPM6/TRPM7-mediated Mg²⁺ transport in CRC progression and emphasize the potential of these channels as therapeutic targets for CRC SP elimination.