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

Sep 28, 2026

Magnesium (Mg2+) regulates enzymatic reactions, DNA replication, oxidative stress responses, and cytoskeletal dynamics, and dysregulated Mg2+ homeostasis is linked to cancer progression, especially colorectal cancer (CRC). TRPM channels, particularly TRPM6 and TRPM7, govern epithelial Mg2+ influx, yet the role of TRPM6 and TRPM6/7 remains unclear. This study examined TRPM6/TRPM6/7 effects on Mg2+ influx, spheroid formation, stemness, and migration in HT-29 models using mass spectrometry and functional assays. Results show elevated TRPM6/TRPM7 in spheroids and strong suppression by TRPM inhibitors, impairing CRC stem-like traits and migration.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages18

Reading Time45 min

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Abstract

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| W | J | G | O | World Journal of
Gastrointestinal Oncology | | --- | --- | --- | --- | --- | Submit a Manuscript: [https://www.f6publishing.com](https://www.f6publishing.com) World J Gastrointest Oncol 2025 December 15; 17(12): 110736 DOI: 10.4251/wjgo.v17.i12.110736 ISSN 1948-5204 (online) ORIGINAL ARTICLE Basic Study 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 Specialty type: Oncology Provenance and peer review: Invited article; Externally peer reviewed. Peer-review model: Single blind Peer-review report’s classification Scientific Quality: Grade B, Grade B, Grade C Novelty: Grade A, Grade B, Grade B Creativity or Innovation: Grade A, Grade B, Grade B Scientific Significance: Grade B, Grade B, Grade B P-Reviewer: Chen ZJ, MD, PhD, Professor, China; Liu T, PhD, Professor, Senior Researcher, China Received: June 16, 2025 Revised: July 8, 2025 Accepted: October 17, 2025 Published online: December 15, 2025 Processing time: 181 Days and 5.7 Hours 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 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.](Thailand. narongritt@buu.ac.th)[ narongritt@buu.ac.th](Thailand. narongritt@buu.ac.th) 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. Func-tionalassays, including secondary SP formation and wound healing, assessed stemness and migration. Cells were treated with Mg2+ transport inhibitors: Co(III)hexamine, WJGO [https://www.wjgnet.com](https://www.wjgnet.com) 1 December 15, 2025 Volume 17 Issue 12 Kampuang N et al. TRPM6/7 inhibition suppress HT-29 cells 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, abolish

FAQs

Why is Mg2+ homeostasis important in colorectal cancer?

Mg2+ supports multiple cellular processes and dysregulated Mg2+ homeostasis is increasingly associated with cancer development and progression, particularly colorectal cancer.

What is the main goal of this study?

To investigate how membrane-localized TRPM6 and TRPM6/7 channels affect Mg2+ influx, spheroid formation, stemness, and migration.

How do TRPM6 and TRPM6/7 antagonists affect HT-29 cells?

Pharmacological inhibition reduces Mg2+ influx, lowers total Mg2+ content, compromises CRC spheroid stability, abolishes cancer stem-like properties, impairs migration, and downregulates pro-tumorigenic markers such as Nanog, COX-2, and MMP-9.

Sep 28, 2026

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