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TGF?-induced epithelial-to-mesenchymal transition in prostate cancer cells is mediated via TRPM7 expression.

ABSTRACT: Growth factors, such as the transforming growth factor beta (TGF?), play an important role in promoting metastasis of prostate cancer, thus understanding how TGF? could induce prostate cancer cell migration may enable us to develop targeted strategies for treatment of advanced metastatic prostate cancer. To more clearly define the mechanism(s) involved in prostate cancer cell migration, we undertook a series of studies utilizing non-malignant prostate epithelial cells RWPE1 and prostate cancer DU145 and PC3 cells. Our studies show that increased cell migration was observed in prostate cancer cells, which was mediated through epithelial-to-mesenchymal transition (EMT). Importantly, addition of Mg²⁺ , but not Ca²⁺ , increased cell migration. Furthermore, TRPM7 expression, which functions as an Mg²⁺ influx channel, was also increased in prostate cancer cells. Inhibition of TRPM7 currents by 2-APB, significantly blocked cell migration in both DU145 and PC3 cells. Addition of growth factor TGF? showed a further increase in cell migration, which was again blocked by the addition of 2-APB. Importantly, TGF? addition also significantly increased TRPM7 expression and function, and silencing of TRPM7 negated TGF?-induced cell migration along with a decrease in EMT markers showing loss of cell adhesion. Furthermore, resveratrol, which decreases prostate cancer cell migration, inhibited TRPM7 expression and function including TGF?-induced cell migration and activation of TRPM7 function. Together, these results suggest that Mg²⁺ influx via TRPM7 promotes cell migration by inducing EMT in prostate cancer cells and resveratrol negatively modulates TRPM7 function thereby inhibiting prostate cancer metastasis.

SUBMITTER: Sun Y

PROVIDER: S-EPMC5947546 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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

Sun Yuyang Y Schaar Anne A Sukumaran Pramod P Dhasarathy Archana A Singh Brij B BB

Molecular carcinogenesis 20180315 6

Growth factors, such as the transforming growth factor beta (TGFβ), play an important role in promoting metastasis of prostate cancer, thus understanding how TGFβ could induce prostate cancer cell migration may enable us to develop targeted strategies for treatment of advanced metastatic prostate cancer. To more clearly define the mechanism(s) involved in prostate cancer cell migration, we undertook a series of studies utilizing non-malignant prostate epithelial cells RWPE1 and prostate cancer D ...[more]

PMID: 29500887

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Project description:A growing body of evidence supports that the epithelial-to-mesenchymal transition (EMT), which occurs during cancer development and progression, has a crucial role in metastasis by enhancing the motility of tumor cells. Transforming growth factor-β (TGF-β) is known to induce EMT in a number of cancer cell types; however, the mechanism underlying this transition process is not fully understood. In this study we have demonstrated that TGF-β upregulates the expression of tumor suppressor protein Par-4 (prostate apoptosis response-4) concomitant with the induction of EMT. Mechanistic investigations revealed that exogenous treatment with each TGF-β isoform upregulates Par-4 mRNA and protein levels in parallel levels of phosphorylated Smad2 and IκB-α increase. Disruption of TGF-β signaling by using ALK5 inhibitor, neutralizing TGF-β antibody or phosphoinositide 3-kinase inhibitor reduces endogenous Par-4 levels, suggesting that both Smad and NF-κB pathways are involved in TGF-β-mediated Par-4 upregulation. NF-κB-binding sites in Par-4 promoter have previously been reported; however, using chromatin immunoprecipitation assay we showed that Par-4 promoter region also contains Smad4-binding site. Furthermore, TGF-β promotes nuclear localization of Par-4. Prolonged TGF-β3 treatment disrupts epithelial cell morphology, promotes cell motility and induces upregulation of Snail, vimentin, zinc-finger E-box binding homeobox 1 and N-Cadherin and downregulation of Claudin-1 and E-Cadherin. Forced expression of Par-4, results in the upregulation of vimentin and Snail expression together with increase in cell migration. In contrast, small interfering RNA-mediated silencing of Par-4 expression results in decrease of vimentin and Snail expression and prevents TGF-β-induced EMT. We have also uncovered a role of X-linked inhibitor of apoptosis protein in the regulation of endogenous Par-4 levels through inhibition of caspase-mediated cleavage. In conclusion, our findings suggest that Par-4 is a novel and essential downstream target of TGF-β signaling and acts as an important factor during TGF-β-induced EMT.

Dataset Information

TGF?-induced epithelial-to-mesenchymal transition in prostate cancer cells is mediated via TRPM7 expression.

Publications

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

Similar Datasets

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