TRPM4 is highly expressed in human colorectal tumor buds and contributes to proliferation, cell cycle, and invasion of colorectal cancer cells

Kappel, Sven; Stokłosa, Paulina; Hauert, Barbara; Ross‐Kaschitza, Daniela; Borgström, Anna; Baur, Roland; Galván, José A.; Zlobec, Inti; Peinelt, Christine

doi:10.1002/1878-0261.12566

Cited by 37 publications

(65 citation statements)

References 39 publications

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“…TRPM4 expression levels have been investigated in a number of different cancers ( Figure 2 ) [ 32 , 33 , 34 , 38 , 39 , 40 , 41 , 101 , 102 , 103 , 104 , 105 , 106 ]. In most studies, TRPM4 protein expression levels were reported to be increased in tumor samples compared to healthy tissue.…”

Section: Trpm4 Expression In Cancermentioning

confidence: 99%

“…However, another study using TRPM4 knockout mice reported no differences in glucose-induced insulin release compared to wild-type mice [ 14 ]. Lately, growing interest has been directed toward TRPM4 and its role in several types of cancer [ 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 ]. TRPM4 contributes to several cancer hallmark functions, such as cell migration, proliferation, and the epithelial to mesenchymal transition (EMT).…”

Section: Introductionmentioning

confidence: 99%

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TRPM4 in Cancer—A New Potential Drug Target

2021

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Transient receptor potential melastatin 4 (TRPM4) is widely expressed in various organs and associated with cardiovascular and immune diseases. Lately, the interest in studies on TRPM4 in cancer has increased. Thus far, TRPM4 has been investigated in diffuse large B-cell lymphoma, prostate, colorectal, liver, breast, urinary bladder, cervical, and endometrial cancer. In several types of cancer TRPM4 is overexpressed and contributes to cancer hallmark functions such as increased proliferation and migration and cell cycle shift. Hence, TRPM4 is a potential prognostic cancer marker and a promising anticancer drug target candidate. Currently, the underlying mechanism by which TRPM4 contributes to cancer hallmark functions is under investigation. TRPM4 is a Ca2+-activated monovalent cation channel, and its ion conductivity can decrease intracellular Ca2+ signaling. Furthermore, TRPM4 can interact with different partner proteins. However, the lack of potent and specific TRPM4 inhibitors has delayed the investigations of TRPM4. In this review, we summarize the potential mechanisms of action and discuss new small molecule TRPM4 inhibitors, as well as the TRPM4 antibody, M4P. Additionally, we provide an overview of TRPM4 in human cancer and discuss TRPM4 as a diagnostic marker and anticancer drug target.

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Section: Trpm4 Expression In Cancermentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

TRPM4 in Cancer—A New Potential Drug Target

2021

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“…Furthermore, TRPM4-mediated Na + influx was shown to regulate cell viability and the cell cycle of HCT116 cells. In the same study, TRPM4 was also linked to the regulation of CRC cells migration and invasion [122].…”

Section: Colorectal Cancermentioning

confidence: 88%

“…For example, TRPM7 is upregulated in pre-malignant pancreatic cancer compared to normal pancreatic tissue [103], and so it could potentially serve as a candidate for a pancreatic cancer biomarker. Another candidate for a novel biomarker could be TRPM4, which was shown to be highly expressed in tumor buds in CRC cancer tissues [122]. Currently, there is a need for the introduction of novel additional biomarkers, which could support the TNM staging system [155].…”

Section: Discussionmentioning

confidence: 99%

TRP Channels in Digestive Tract Cancers

Stokłosa

Borgström

Kappel

et al. 2020

IJMS

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Cancers of the digestive tract are among the most prevalent types of cancer. These types of cancers are often diagnosed at a late stage, which results in a poor prognosis. Currently, many biomedical studies focus on the role of ion channels, in particular transient receptor potential (TRP) channels, in cancer pathophysiology. TRP channels show mostly non-selective permeability to monovalent and divalent cations. TRP channels are often dysregulated in digestive tract cancers, which can result in alterations of cancer hallmark functions, such as enhanced proliferation, migration, invasion and the inability to induce apoptosis. Therefore, TRP channels could serve as potential diagnostic biomarkers. Moreover, TRP channels are mostly expressed on the cell surface and ion channel targeting drugs do not need to enter the cell, making them attractive candidate drug targets. In this review, we summarize the current knowledge about TRP channels in connection to digestive tract cancers (oral cancer, esophageal cancer, liver cancer, pancreatic cancer, gastric cancer and colorectal cancer) and give an outlook on the potential of TRP channels as cancer biomarkers or therapeutic targets.

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“…Indeed, other KCTD proteins regulate ion channels function [ 40 , 61 , 62 ]. Interestingly, KCTD5 is involved in the regulation of TRPM4 activity, a well-described ion channel related to cell migration [ 40 , 41 , 63 , 64 , 65 ]. Therefore, it could be plausible that the KCTD5-dependent effects in Ca 2+ response are the result of the action of KCTD5 on the ion channels function.…”

Section: Discussionmentioning

confidence: 99%

K+ Channel Tetramerization Domain 5 (KCTD5) Protein Regulates Cell Migration, Focal Adhesion Dynamics and Spreading through Modulation of Ca2+ Signaling and Rac1 Activity

Canales

Cruz

Díaz

et al. 2020

Cells

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Cell migration is critical for several physiological and pathophysiological processes. It depends on the coordinated action of kinases, phosphatases, Rho-GTPases proteins, and Ca2+ signaling. Interestingly, ubiquitination events have emerged as regulatory elements of migration. Thus, the role of proteins involved in ubiquitination processes could be relevant to a complete understanding of pro-migratory mechanisms. KCTD5 is a member of Potassium Channel Tetramerization Domain (KCTD) proteins that have been proposed as a putative adaptor for Cullin3-E3 ubiquitin ligase and a novel regulatory protein of TRPM4 channels. Here, we study whether KCTD5 participates in cell migration-associated mechanisms, such as focal adhesion dynamics and cellular spreading. Our results show that KCTD5 CRISPR/Cas9- and shRNA-based depletion in B16-F10 cells promoted an increase in cell migration and cell spreading, and a decrease in the focal adhesion area, consistent with an increased focal adhesion disassembly rate. The expression of a dominant-negative mutant of Rho-GTPases Rac1 precluded the KCTD5 depletion-induced increase in cell spreading. Additionally, KCTD5 silencing decreased the serum-induced Ca2+ response, and the reversion of this with ionomycin abolished the KCTD5 knockdown-induced decrease in focal adhesion size. Together, these data suggest that KCTD5 acts as a regulator of cell migration by modulating cell spreading and focal adhesion dynamics through Rac1 activity and Ca2+ signaling, respectively.

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TRPM4 is highly expressed in human colorectal tumor buds and contributes to proliferation, cell cycle, and invasion of colorectal cancer cells

Abstract: Abbreviations CD, current density; CRC, colorectal cancer; TBC, tumor border configuration; TRPM4, transient receptor potential melastatin-4 channel.

Cited by 37 publications

References 39 publications

TRPM4 in Cancer—A New Potential Drug Target

TRPM4 in Cancer—A New Potential Drug Target

TRP Channels in Digestive Tract Cancers

K+ Channel Tetramerization Domain 5 (KCTD5) Protein Regulates Cell Migration, Focal Adhesion Dynamics and Spreading through Modulation of Ca2+ Signaling and Rac1 Activity

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