TGFβ‐induced epithelial‐to‐mesenchymal transition in prostate cancer cells is mediated via TRPM7 expression

Sun, Yuyang; Schaar, Anne; Sukumaran, Pramod; Dhasarathy, Archana; Singh, Brij B.

doi:10.1002/mc.22797

Cited by 44 publications

(48 citation statements)

References 62 publications

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“…TRPM7 knockdown can disorganize cytoskeleton in mesenchymal MDA-MB-231 which lose their spindle-shaped morphology (Middelbeek et al 2012). TRPM7 is also known to participate in the epithelial-to-mesenchymal transition (EMT) in breast cancer (Davis et al 2014;Kuipers et al 2018;Sun et al 2018). In the present study, we also demonstrate that Cd 2+ exposure increases EMT markers N-Cadherin and Vimentin, while E-Cadherin is decreased in mammary epithelial cells.…”

Section: Discussionsupporting

confidence: 70%

Cadmium exposure enhances cell migration and invasion through modulated TRPM7 channel expression

et al. 2020

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Cadmium is a xenobiotic involved in neoplastic transformation. Cadmium enters the cells through divalent cation transporters including the Transient Receptor Potential Melastatin-related 7 (TRPM7) which is known to be involved in cancer cell fate. This work aimed to study the role of TRPM7 in neoplastic transformation induced by cadmium exposure in non-cancer epithelial cells. Non-cancer epithelial cells were chronically exposed to low-dose of cadmium. TRPM7 expression and function were studied by Western-Blot, Patch-Clamp and calcium and magnesium imaging. Finally, cell migration and invasion were studied by Boyden chamber assays. Chronic cadmium exposure induced TRPM7 overexpression and increased the membrane currents (P < 0.001). Cells exposed to cadmium had higher intracellular calcium and magnesium levels (P < 0.05). TRPM7 silencing restored calcium levels but strongly decreased intracellular magnesium concentration (P < 0.001). Moreover, cadmium exposure enhanced both cell migration and invasion, but TRPM7 silencing strongly decreased these features (P < 0.001). Furthermore, mammary epithelial cells exposed to cadmium became rounded and had less cell-to-cell junctions. Cadmium exposure decreased epithelial markers while the mesenchymal ones were increased. Importantly, TRPM7 silencing was able to reverse these phenotypic modifications (P < 0.05). To summarize, our data show that chronic cadmium exposure enhanced TRPM7 expression and activity in non-cancer epithelial cells. TRPM7 overexpression induced intracellular magnesium increase and stimulated cell migration and invasion. These neoplastic properties could be linked to a TRPM7dependent epithelial-to-mesenchymal transition reprogramming in cell exposed to cadmium. These findings provide new insights into the regulation of cell fates by cadmium exposure. Keywords Cadmium • TRPM7 • Magnesium • Cell invasion • EMT Abbreviations BCA Bicinchoninic acid Ca 2+ Calcium Cd 2+ Cadmium DMEM/F-12 Dulbecco's modified Eagle's medium/ nutrient mixture F-12 DMSO Dimethyl sulfoxide EDTA Ethylenediaminetetraacetic acid EGTA Ethylene glycol-bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid EMT Epithelial-to-mesenchymal transition ER Estrogen receptor FCS Fetal calf serum Mg 2+ Magnesium Mn 2+ Manganese MIC Magnesium inhibited cation MTT 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide SDS Sodium dodecyl sulfate siControl Scrambled small interfering RNA Electronic supplementary material The online version of this article (

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Section: Discussionsupporting

confidence: 70%

Cadmium exposure enhances cell migration and invasion through modulated TRPM7 channel expression

et al. 2020

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“…Here, our study also verified hypoxia insult caused a decrease of E-Cad protein expression, whereas an increase of N-Cad and vimentin protein expression. Reduction of HIF-1α, as well as downregulation of TRPM7, inhibited EMT and invasion of prostate cancer cells [15,16,42]. Our study is consistent with these findings, also showed that knockdown of both TRPM7 and HIF-1α inhibited EMT changes of androgen-independent prostate cancer cells induced by hypoxia, suggesting that TRPM7 regulates HIF-1α-mediated signaling to affect hypoxia-induced EMT in androgen-independent prostate cancer cells.…”

supporting

confidence: 91%

“…Downregulation of TRPM7 inhibited migration and invasion of prostate cancer cells with a mechanism involved in the regulation of epithelialmesenchymal transition (EMT) [15]. Besides, TRPM7 also mediated transforming growth factor beta-(TGF β-) induced EMT in prostate cancer [16]. TRPM7 overexpression was induced by hypoxia-ischemia in the rodent brain and mediated the corresponding brain injury, serving as a potential drug target for stroke [17].…”

Section: Introductionmentioning

confidence: 99%

Suppression of TRPM7 Inhibited Hypoxia-Induced Migration and Invasion of Androgen-Independent Prostate Cancer Cells by Enhancing RACK1-Mediated Degradation of HIF-1α

Yang

Cai

Zhan

et al. 2020

Oxidative Medicine and Cellular Longevity

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Transient receptor potential melastatin subfamily member 7 (TRPM7) was essential in the growth and metastatic ability of prostate cancer cells. However, the effects and the relevant molecular mechanisms of TRPM7 on metastasis of prostate cancer under hypoxic atmosphere remain unclear. This study investigated the role of TRPM7 in the metastatic ability of androgen-independent prostate cancer cells under hypoxia. First, data mining was carried out to disclose the relationship between the TRPM7 gene level and the survival of prostate cancer patients. Specific siRNAs were used to knockdown target genes. Western blotting and qPCR were employed to determine protein and gene expression, respectively. The gene transcription activity was evaluated by luciferase activity assay of promoter gene. The protein interaction was determined by coimmunoprecipitation. Wound healing and transwell assays were employed to evaluated cell migration and invasion, respectively. Open access database results showed that high expression of TRPM7 was closely related to the poor survival of prostate cancer patients. Hypoxia simultaneously increased TRPM7 expression and induced HIF-1α accumulation in androgen-independent prostate cancer cells. Knockdown of TRPM7 significantly promoted HIF-1α degradation through the proteasome and inhibited EMT changes in androgen-independent prostate cancer cells under hypoxic condition. Moreover, TRPM7 knockdown increased the phosphorylation of RACK1 and strengthened the interaction between RACK1 and HIF-1α but attenuated the binding of HSP90 to HIF-1α. Whereas knockdown of RACK1 increased the binding of HSP90 to HIF-1α. Furthermore, both TRPM7 and HIF-1α knockdown significantly suppressed hypoxia-induced Annexin A1 protein expression, and suppression of HIF-1α/Annexin A1 signaling significantly inhibited hypoxia-induced cell migration and invasion of androgen-independent prostate cancer cells. Our findings demonstrate that TRPM7 knockdown promotes HIF-1α degradation via an oxygen-independent mechanism involving increased binding of RAKC1 to HIF-1α, and TRPM7-HIF-1α-Annexin A1 signaling axis plays a crucial role in the EMT, cell migration, and invasion of androgen-independent prostate cancer cells under hypoxic conditions.

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“…These inhibitory NF-κβ effects could not be reversed by the incubation of cells with TGF-β, suggesting that these factors may synergistically induce invasion and EMT in prostate cancer cells [253]. TGF-β-mediated EMT can also be inhibited by Elf5 (through suppression of SMAD3 phosphorylation [254] or FoxA1 [255], and induced by SOX5 [105], CML, CRM1 [256], TRPM7 [257], or SENP1. Interestingly, the latter effect involves SENP1-induced deSUMOylation of SMAD4, leading to its inhibition and induction of EMT [258].…”

Section: Prostate Cancermentioning

confidence: 99%

TGF-β and microRNA Interplay in Genitourinary Cancers

Bogusławska¹,

Kryst

Poletajew

et al. 2019

Cells

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Genitourinary cancers (GCs) include a large group of different types of tumors localizing to the kidney, bladder, prostate, testis, and penis. Despite highly divergent molecular patterns, most GCs share commonly disturbed signaling pathways that involve the activity of TGF-β (transforming growth factor beta). TGF-β is a pleiotropic cytokine that regulates key cancer-related molecular and cellular processes, including proliferation, migration, invasion, apoptosis, and chemoresistance. The understanding of the mechanisms of TGF-β actions in cancer is hindered by the “TGF-β paradox” in which early stages of cancerogenic process are suppressed by TGF-β while advanced stages are stimulated by its activity. A growing body of evidence suggests that these paradoxical TGF-β actions could result from the interplay with microRNAs: Short, non-coding RNAs that regulate gene expression by binding to target transcripts and inducing mRNA degradation or inhibition of translation. Here, we discuss the current knowledge of TGF-β signaling in GCs. Importantly, TGF-β signaling and microRNA-mediated regulation of gene expression often act in complicated feedback circuits that involve other crucial regulators of cancer progression (e.g., androgen receptor). Furthermore, recently published in vitro and in vivo studies clearly indicate that the interplay between microRNAs and the TGF-β signaling pathway offers new potential treatment options for GC patients.

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TGFβ‐induced epithelial‐to‐mesenchymal transition in prostate cancer cells is mediated via TRPM7 expression

Cited by 44 publications

References 62 publications

Cadmium exposure enhances cell migration and invasion through modulated TRPM7 channel expression

Cadmium exposure enhances cell migration and invasion through modulated TRPM7 channel expression

Suppression of TRPM7 Inhibited Hypoxia-Induced Migration and Invasion of Androgen-Independent Prostate Cancer Cells by Enhancing RACK1-Mediated Degradation of HIF-1α

TGF-β and microRNA Interplay in Genitourinary Cancers

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