Inhibition of TRPM7 blocks MRTF/SRF-dependent transcriptional and tumorigenic activity

Voringer, Sandra; Schreyer, Laura; Nadolni, Wiebke; Meier, Melanie; Woerther, Katharina; Mittermeier, Constanze; Ferioli, Silvia; Singer, Stephan; Hölzer, Kerstin; Zierler, Susanna; Chubanov, Vladimir; Liebl, Bernhard; Gudermann, Thomas; Muehlich, Susanne

doi:10.1038/s41388-019-1140-8

Cited by 35 publications

(43 citation statements)

References 47 publications

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“…34 The myocardin-related transcription factors A and B-SRF pathway is of great significance for cell proliferation, motility, and adhesion, which were all major processes underlying the progression of cancers. 35 For instance, SRF expedited gastric cancer metastasis by accelerating myofibroblast-cancer cell crosstalk. 36 More specifically, SRF was monitored to transactivate miR-199a-5p and miR- 199a-3p by interacting with their promoters in a direct manner to modulate epithelial-mesenchymal-transition and pulmonary metastases.…”

Section: Discussionmentioning

confidence: 99%

<p>SRF Potentiates Colon Cancer Metastasis and Progression in a microRNA-214/PTK6-Dependent Manner</p>

Li¹,

Wan²,

Su³

et al. 2020

CMAR

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Serum response factor (SRF), a sequence-specific transcription factor, is closely related to metastasis of gastric cancer, a digestive tract cancer. Herein, we probed the effect of SRF on metastasis and progression of colon cancer (CC), another digestive tract disorder, and the detailed mechanism. Methods: Microarray analysis was conducted on tumor and adjacent tissues to filter differentially expressed miRNA, followed by RT-qPCR validation in CC cell lines. The transcription factor and the target gene of microRNA-214 (miR-214) were predicted, and their binding relationships were tested by luciferase reporter assays and ChIP assays. Subsequently, SRF and protein tyrosine kinase 6 (PTK6) expression in CC patients and cells was evaluated by RT-qPCR, while JAK2 and STAT3 expression in cells by Western blot analysis. To further explore functions of miR-214, PTK6 and SRF on CC, CC cells were delivered with si-PTK6, miR-214 mimic and/or SRF overexpression. Results: miR-214 expressed poorly in CC tissues and cell lines, which related to advanced TNM staging and survival. miR-214 mimic inhibited proliferation, migration, invasion, xenograft tumor growth and metastasis of CC cells. SRF, overexpressed in CC samples and cells, suppressed the transcription of miR-214. Meanwhile, SRF upregulation counteracted the inhibitory role of miR-214 mimic in CC cell growth. miR-214 negatively regulated PTK6 expression to impair the JAK2/STAT3 pathway activation, thereby halting CC cell proliferation, migration, invasion, xenograft tumor growth and metastasis. Conclusion: Altogether, miR-214 may perform as a tumor suppressor in CC, and the SRF/ miR-214/PTK6/JAK2/STAT3 axis could be applied as a biomarker and potential therapeutic target.

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Section: Discussionmentioning

confidence: 99%

<p>SRF Potentiates Colon Cancer Metastasis and Progression in a microRNA-214/PTK6-Dependent Manner</p>

Li¹,

Wan²,

Su³

et al. 2020

CMAR

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“…The list of phosphorylation substrates of the TRPM7 kinase is extensive and surprisingly heterogeneous in terms of possible biochemical pathways affected. Thus, TRPM7 kinase can phosphorylate TRPM6 [ 68 ], annexin A1 [ 69 ], myosin II isoforms [ 70 ], eukaryotic elongation factor-2 kinase (eEF2-k) [ 71 ], tropomodulin [ 72 ], phospholipase C gamma 2 (PLCγ2) [ 73 ], stromal interaction molecule 2 (STIM2) [ 25 ], Mothers against decapentaplegic homolog 2 (SMAD2) [ 59 ], and Ras homolog family member A (RhoA) [ 74 ]. Furthermore, multiple serine/threonine residues positioned in a ‘substrate’ segment of TRPM7 are autophosphorylation targets of the kinase domain [ 11 , 75 , 76 , 77 ].…”

Section: Functional Characteristics and Physiological Roles Of Trpmentioning

confidence: 99%

“…As discussed above, TRPM7 inhibitors showed anti-proliferative effects on many cultured tumour-derived cells. Recently, our laboratory explored hepatocellular carcinoma HuH7 cells in a xenograft mouse model to assess the efficiency of NS8593 to suppress tumour progression ( Table 1 ) [ 74 ]. Thus, we treated nude mice bearing xenografts derived from HuH7 cells systemically by intravenous injection of NS85936 (6 mg/kg every 2nd day, 17 days) and observed profoundly reduced tumour growth in NS85936-treated mice when compared with control animals [ 74 ].…”

Section: Assessment Of Ns8593 Effects In Animal Modelsmentioning

confidence: 99%

“…Recently, our laboratory explored hepatocellular carcinoma HuH7 cells in a xenograft mouse model to assess the efficiency of NS8593 to suppress tumour progression ( Table 1 ) [ 74 ]. Thus, we treated nude mice bearing xenografts derived from HuH7 cells systemically by intravenous injection of NS85936 (6 mg/kg every 2nd day, 17 days) and observed profoundly reduced tumour growth in NS85936-treated mice when compared with control animals [ 74 ]. Further experiments with multiple cell models revealed that the anti-tumour effect of NS8593 relies on TRPM7 channel-mediated Mg 2+ influx and phosphorylation of RhoA by TRPM7 kinase [ 74 ].…”

Section: Assessment Of Ns8593 Effects In Animal Modelsmentioning

confidence: 99%

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Mapping TRPM7 Function by NS8593

Chubanov¹,

Gudermann²

2020

IJMS

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The transient receptor potential cation channel, subfamily M, member 7 (TRPM7) is a ubiquitously expressed membrane protein, which forms a channel linked to a cytosolic protein kinase. Genetic inactivation of TRPM7 in animal models uncovered the critical role of TRPM7 in early embryonic development, immune responses, and the organismal balance of Zn2+, Mg2+, and Ca2+. TRPM7 emerged as a new therapeutic target because malfunctions of TRPM7 have been associated with anoxic neuronal death, tissue fibrosis, tumour progression, and giant platelet disorder. Recently, several laboratories have identified pharmacological compounds allowing to modulate either channel or kinase activity of TRPM7. Among other small molecules, NS8593 has been defined as a potent negative gating regulator of the TRPM7 channel. Consequently, several groups applied NS8593 to investigate cellular pathways regulated by TRPM7. Here, we summarize the progress in this research area. In particular, two notable milestones have been reached in the assessment of TRPM7 druggability. Firstly, several laboratories demonstrated that NS8593 treatment reliably mirrors prominent phenotypes of cells manipulated by genetic inactivation of TRPM7. Secondly, it has been shown that NS8593 allows us to probe the therapeutic potential of TRPM7 in animal models of human diseases. Collectively, these studies employing NS8593 may serve as a blueprint for the preclinical assessment of TRPM7-targeting drugs.

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“…This suggests a role for TRPM7 in aggressive phenotypes in neuroblastoma cells via p116RIP-mediated RhoA/ROCK regulation and subsequent changes in cytoskeleton dynamics. Also, a functional coupling between TRPM7 and RhoA activation dependent on the TRPM7 kinase activity on hepatocellular carcinoma has been shown ( Voringer et al, 2020 ). These data support a TRPM7-mediated RhoA activation involvement in diverse processes such as the inhibition of axonal growth cone and the migratory phenotype of brain tumor cells like neuroblastoma ( Figure 3 ).…”

Section: Trp Channelsmentioning

confidence: 99%