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The acquisition of invasive capacities by carcinoma cells, i.e. their ability to migrate through and to remodel extracellular matrices, is a determinant process leading to their dissemination and to the development of metastases. these cancer cell properties have often been associated with an increased Rho-ROCK signalling, and ROCK inhibitors have been proposed for anticancer therapies. In this study we used the selective ROCK inhibitor, Y-27632, to address the participation of the Rho-ROCK signalling pathway in the invasive properties of SW620 human colon cancer cells. Contrarily to initial assumptions, Y-27632 induced the acquisition of a pro-migratory cell phenotype and increased cancer cell invasiveness in both 3- and 2-dimensions assays. This effect was also obtained using the other ROCK inhibitor Fasudil as well as with knocking down the expression of ROCK-1 or ROCK-2, but was prevented by the inhibition of Na V 1.5 voltage-gated sodium channel activity. Indeed, ROCK inhibition enhanced the activity of the pro-invasive Na V 1.5 channel through a pathway that was independent of gene expression regulation. In conclusions, our evidence identifies voltage-gated sodium channels as new targets of the ROCK signalling pathway, as well as responsible for possible deleterious effects of the use of ROCK inhibitors in the treatment of cancers.

The development of metastases largely relies on the capacity of cancer cells to invade extracellular matrices (ECM) using two invasion modes termed ‘mesenchymal’ and ‘amoeboid’, with possible transitions between these modes. Here we show that the SCN4B gene, encoding for the β4 protein, initially characterized as an auxiliary subunit of voltage-gated sodium channels (Na V ) in excitable tissues, is expressed in normal epithelial cells and that reduced β4 protein levels in breast cancer biopsies correlate with high-grade primary and metastatic tumours. In cancer cells, reducing β4 expression increases RhoA activity, potentiates cell migration and invasiveness, primary tumour growth and metastatic spreading, by promoting the acquisition of an amoeboid–mesenchymal hybrid phenotype. This hyperactivated migration is independent of Na V and is prevented by overexpression of the intracellular C-terminus of β4. Conversely, SCN4B overexpression reduces cancer cell invasiveness and tumour progression, indicating that SCN4B /β4 represents a metastasis-suppressor gene. The capacity of cancer cells to migrate is intimately linked to their ability to induce metastasis. Here the authors show that the sodium channel β4 subunit regulates breast cancer cell migration via inhibition of RhoA activation, independently from its function as an auxiliary protein of the sodium channel.

Dysregulated RNA metabolism caused by SMN deficiency leads to motor neuron disease spinal muscular atrophy (SMA). Current therapies improve patient outcomes but achieve no definite cure, prompting renewed efforts to better understand disease mechanisms. The calcium channel blocker flunarizine improves motor function in Smn-deficient mice and can help uncover neuroprotective pathways. Murine motor neuron-like NSC34 cells were used to study the molecular cell-autonomous mechanism. Following RNA and protein extraction, RT-qPCR and immunodetection experiments were performed. The relationship between flunarizine mRNA targets and RNA-binding protein GEMIN5 was explored by RNA-immunoprecipitation. Flunarizine increases demethylase Kdm6b transcripts across cell cultures and mouse models. It causes, in NSC34 cells, a temporal expression of GEMIN5 and KDM6B. GEMIN5 binds to flunarizine-modulated mRNAs, including Kdm6b transcripts. Gemin5 depletion reduces Kdm6b mRNA and protein levels and hampers responses to flunarizine, including neurite extension in NSC34 cells. Moreover, flunarizine increases the axonal extension of motor neurons derived from SMA patient-induced pluripotent stem cells. Finally, immunofluorescence studies of spinal cord motor neurons in Smn-deficient mice reveal that flunarizine modulates the expression of KDM6B and its target, the motor neuron-specific transcription factor HB9, driving motor neuron maturation. Our study reveals GEMIN5 regulates Kdm6b expression with implications for motor neuron diseases and therapy.

Background Na V 1.5 voltage-gated sodium channels are abnormally expressed in breast tumours and their expression level is associated with metastatic occurrence and patients’ death. In breast cancer cells, Na V 1.5 activity promotes the proteolytic degradation of the extracellular matrix and enhances cell invasiveness. Findings In this study, we showed that the extinction of Na V 1.5 expression in human breast cancer cells almost completely abrogated lung colonisation in immunodepressed mice (NMRI nude). Furthermore, we demonstrated that ranolazine (50 μM) inhibited Na V 1.5 currents in breast cancer cells and reduced Na V 1.5-related cancer cell invasiveness in vitro. In vivo , the injection of ranolazine (50 mg/kg/day) significantly reduced lung colonisation by Na V 1.5-expressing human breast cancer cells. Conclusions Taken together, our results demonstrate the importance of Na V 1.5 in the metastatic colonisation of organs by breast cancer cells and indicate that small molecules interfering with Na V activity, such as ranolazine, may represent powerful pharmacological tools to inhibit metastatic development and improve cancer treatments.

Peroxisome proliferator-activated receptor β (PPARβ) and Na V 1.5 voltage-gated sodium channels have independently been shown to regulate human breast cancer cell invasiveness. The n-3 polyunsaturated docosahexaenoic acid (DHA, 22:6n-3), a natural ligand of PPAR, is effective in increasing survival and chemotherapy efficacy in breast cancer patient with metastasis. DHA reduces breast cancer cell invasiveness and it also inhibits PPARβ expression. We have shown previously that Na V 1.5 promotes MDA-MB-231 breast cancer cells invasiveness by potentiating the activity of Na + /H + exchanger type 1 (NHE-1), the major regulator of H + efflux in these cells. We report here that DHA inhibited Na V 1.5 current and NHE-1 activity in human breast cancer cells, and in turn reduced Na V 1.5-dependent cancer cell invasiveness. For the first time, we show that antagonizing PPARβ, or inhibiting its expression, reduced Na V 1.5 mRNA and protein expression and Na V 1.5 current, as well as NHE-1 activity and cell invasiveness. Consistent with these results, the DHA-induced reduction of both Na V 1.5 expression and NHE-1 activity was abolished in cancer cells knocked-down for the expression of PPARβ (shPPARβ). This demonstrates a direct link between the inhibition of PPARβ expression and the inhibition of Nav1.5/NHE-1 activities and breast cancer cell invasiveness. This study provides new mechanistic data advocating for the use of natural fatty acids such as DHA to block the development of breast cancer metastases.

The acquisition of invasive capacities by carcinoma cells, i.e. their ability to migrate through and to remodel extracellular matrices, is a determinant process leading to their dissemination and to the development of metastases. these cancer cell properties have often been associated with an increased Rho-ROCK signalling, and ROCK inhibitors have been proposed for anticancer therapies. In this study we used the selective ROCK inhibitor, Y-27632, to address the participation of the Rho-ROCK signalling pathway in the invasive properties of SW620 human colon cancer cells. Contrarily to initial assumptions, Y-27632 induced the acquisition of a pro-migratory cell phenotype and increased cancer cell invasiveness in both 3- and 2-dimensions assays. This effect was also obtained using the other ROCK inhibitor Fasudil as well as with knocking down the expression of ROCK-1 or ROCK-2, but was prevented by the inhibition of Na 1.5 voltage-gated sodium channel activity. Indeed, ROCK inhibition enhanced the activity of the pro-invasive Na 1.5 channel through a pathway that was independent of gene expression regulation. In conclusions, our evidence identifies voltage-gated sodium channels as new targets of the ROCK signalling pathway, as well as responsible for possible deleterious effects of the use of ROCK inhibitors in the treatment of cancers.

Peroxisome proliferator-activated receptor [beta] (PPAR[beta]) and Na^sub V^1.5 voltage-gated sodium channels have independently been shown to regulate human breast cancer cell invasiveness. The n-3 polyunsaturated docosahexaenoic acid (DHA, 22:6n-3), a natural ligand of PPAR, is effective in increasing survival and chemotherapy efficacy in breast cancer patient with metastasis. DHA reduces breast cancer cell invasiveness and it also inhibits PPAR[beta] expression. We have shown previously that Na^sub V^1.5 promotes MDA-MB-231 breast cancer cells invasiveness by potentiating the activity of Na^sup +^/H^sup +^ exchanger type 1 (NHE-1), the major regulator of H^sup +^ efflux in these cells. We report here that DHA inhibited Na^sub V^1.5 current and NHE-1 activity in human breast cancer cells, and in turn reduced Na^sub V^1.5-dependent cancer cell invasiveness. For the first time, we show that antagonizing PPAR[beta], or inhibiting its expression, reduced Na^sub V^1.5 mRNA and protein expression and Na^sub V^1.5 current, as well as NHE-1 activity and cell invasiveness. Consistent with these results, the DHA-induced reduction of both Na^sub V^1.5 expression and NHE-1 activity was abolished in cancer cells knocked-down for the expression of PPAR[beta] (shPPAR[beta]). This demonstrates a direct link between the inhibition of PPAR[beta] expression and the inhibition of Nav1.5/NHE-1 activities and breast cancer cell invasiveness. This study provides new mechanistic data advocating for the use of natural fatty acids such as DHA to block the development of breast cancer metastases.

Doc number: 264 Abstract Background: NaV 1.5 voltage-gated sodium channels are abnormally expressed in breast tumours and their expression level is associated with metastatic occurrence and patients' death. In breast cancer cells, NaV 1.5 activity promotes the proteolytic degradation of the extracellular matrix and enhances cell invasiveness. Findings: In this study, we showed that the extinction of NaV 1.5 expression in human breast cancer cells almost completely abrogated lung colonisation in immunodepressed mice (NMRI nude). Furthermore, we demonstrated that ranolazine (50 μM) inhibited NaV 1.5 currents in breast cancer cells and reduced NaV 1.5-related cancer cell invasiveness in vitro. In vivo , the injection of ranolazine (50 mg/kg/day) significantly reduced lung colonisation by NaV 1.5-expressing human breast cancer cells. Conclusions: Taken together, our results demonstrate the importance of NaV 1.5 in the metastatic colonisation of organs by breast cancer cells and indicate that small molecules interfering with NaV activity, such as ranolazine, may represent powerful pharmacological tools to inhibit metastatic development and improve cancer treatments.