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1.
EMBO J ; 42(13): e112198, 2023 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-37278161

RESUMO

There is growing evidence that ion channels are critically involved in cancer cell invasiveness and metastasis. However, the molecular mechanisms of ion signaling promoting cancer behavior are poorly understood and the complexity of the underlying remodeling during metastasis remains to be explored. Here, using a variety of in vitro and in vivo techniques, we show that metastatic prostate cancer cells acquire a specific Na+ /Ca2+ signature required for persistent invasion. We identify the Na+ leak channel, NALCN, which is overexpressed in metastatic prostate cancer, as a major initiator and regulator of Ca2+ oscillations required for invadopodia formation. Indeed, NALCN-mediated Na+ influx into cancer cells maintains intracellular Ca2+ oscillations via a specific chain of ion transport proteins including plasmalemmal and mitochondrial Na+ /Ca2+ exchangers, SERCA and store-operated channels. This signaling cascade promotes activity of the NACLN-colocalized proto-oncogene Src kinase, actin remodeling and secretion of proteolytic enzymes, thus increasing cancer cell invasive potential and metastatic lesions in vivo. Overall, our findings provide new insights into an ion signaling pathway specific for metastatic cells where NALCN acts as persistent invasion controller.


Assuntos
Neoplasias da Próstata , Sódio , Masculino , Humanos , Sódio/metabolismo , Canais Iônicos/metabolismo , Transporte de Íons , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo
2.
Nat Commun ; 13(1): 956, 2022 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-35177596

RESUMO

Cellular senescence is implicated in a great number of diseases including cancer. Although alterations in mitochondrial metabolism were reported as senescence drivers, the underlying mechanisms remain elusive. We report the mechanism altering mitochondrial function and OXPHOS in stress-induced senescent fibroblasts. We demonstrate that TRPC3 protein, acting as a controller of mitochondrial Ca2+ load via negative regulation of IP3 receptor-mediated Ca2+ release, is down regulated in senescence regardless of the type of senescence inducer. This remodelling promotes cytosolic/mitochondrial Ca2+ oscillations and elevates mitochondrial Ca2+ load, mitochondrial oxygen consumption rate and oxidative phosphorylation. Re-expression of TRPC3 in senescent cells diminishes mitochondrial Ca2+ load and promotes escape from OIS-induced senescence. Cellular senescence evoked by TRPC3 downregulation in stromal cells displays a proinflammatory and tumour-promoting secretome that encourages cancer epithelial cell proliferation and tumour growth in vivo. Altogether, our results unravel the mechanism contributing to pro-tumour behaviour of senescent cells.


Assuntos
Carcinogênese/patologia , Neoplasias/patologia , Canais de Cátion TRPC/metabolismo , Cálcio/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Senescência Celular , Retículo Endoplasmático/metabolismo , Células HEK293 , Humanos , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Mitocôndrias/metabolismo , Fosforilação Oxidativa , Cultura Primária de Células
3.
Cells ; 10(11)2021 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-34831241

RESUMO

Store-operated calcium entry (SOCE) provided through channels formed by ORAI proteins is a major regulator of several cellular processes. In immune cells, it controls fundamental processes such as proliferation, cell adhesion, and migration, while in cancer, SOCE and ORAI1 gene expression are dysregulated and lead to abnormal migration and/or cell proliferation. In the present study, we used the CRISPR/Cas9 technique to delete the ORAI1 gene and to identify its role in proliferative and migrative properties of the model cell line HEK-293. We showed that ORAI1 deletion greatly reduced SOCE. Thereby, we found that this decrease and the absence of ORAI1 protein did not affect HEK-293 proliferation. In addition, we determined that ORAI1 suppression did not affect adhesive properties but had a limited impact on HEK-293 migration. Overall, we showed that ORAI1 and SOCE are largely dispensable for cellular proliferation, migration, and cellular adhesion of HEK-293 cells. Thus, despite its importance in providing Ca2+ entry in non-excitable cells, our results indicate that the lack of SOCE does not deeply impact HEK-293 cells. This finding suggests the existence of compensatory mechanism enabling the maintenance of their physiological function.


Assuntos
Cálcio/metabolismo , Movimento Celular , Técnicas de Inativação de Genes , Proteína ORAI1/deficiência , Canais de Cálcio/genética , Canais de Cálcio/metabolismo , Adesão Celular , Proliferação de Células , Genoma Humano , Células HEK293 , Humanos , Proteína ORAI1/metabolismo , Proteína ORAI2/genética , Proteína ORAI2/metabolismo
4.
Cancers (Basel) ; 11(7)2019 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-31288452

RESUMO

Background: Transient receptor potential (TRP) channels control multiple processes involved in cancer progression by modulating cell proliferation, survival, invasion and intravasation, as well as, endothelial cell (EC) biology and tumor angiogenesis. Nonetheless, a complete TRP expression signature in tumor vessels, including in prostate cancer (PCa), is still lacking. Methods: In the present study, we profiled by qPCR the expression of all TRP channels in human prostate tumor-derived ECs (TECs) in comparison with TECs from breast and renal tumors. We further functionally characterized the role of the 'prostate-associated' channels in proliferation, sprout formation and elongation, directed motility guiding, as well as in vitro and in vivo morphogenesis and angiogenesis. Results: We identified three 'prostate-associated' genes whose expression is upregulated in prostate TECs: TRPV2 as a positive modulator of TEC proliferation, TRPC3 as an endothelial PCa cell attraction factor and TRPA1 as a critical TEC angiogenic factor in vitro and in vivo. Conclusions: We provide here the full TRP signature of PCa vascularization among which three play a profound effect on EC biology. These results contribute to explain the aggressive phenotype previously observed in PTEC and provide new putative therapeutic targets.

5.
Mol Carcinog ; 56(8): 1851-1867, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28277613

RESUMO

Previous studies showed the effects of resveratrol (RES) on several cancer cells, including prostate cancer (PCa) cell apoptosis without taking into consideration the impact of the tumor microenvironment (TME). The TME is composed of cancer cells, endothelial cells, blood cells, and cancer-associated fibroblasts (CAF), the main source of growth factors. The latter cells might modify in the TME the impact of RES on tumor cells via secreted factors. Recent data clearly show the impact of CAF on cancer cells apoptosis resistance via secreted factors. However, the effects of RES on PCa CAF have not been studied so far. We have investigated here for the first time the effects of RES on the physiology of PCa CAF in the context of TME. Using a prostate cancer CAF cell line and primary cultures of CAF from prostate cancers, we show that RES activates the N-terminal mutated Transient Receptor Potential Ankyrin 1 (TRPA1) channel leading to an increase in intracellular calcium concentration and the expression and secretion of growth factors (HGF and VEGF) without inducing apoptosis in these cells. Interestingly, in the present work, we also show that when the prostate cancer cells were co-cultured with CAF, the RES-induced cancer cell apoptosis was reduced by 40%, an apoptosis reduction canceled in the presence of the TRPA1 channel inhibitors. The present work highlights CAF TRPA1 ion channels as a target for RES and the importance of the channel in the epithelial-stromal crosstalk in the TME leading to resistance to the RES-induced apoptosis.


Assuntos
Anticarcinógenos/farmacologia , Antioxidantes/farmacologia , Canais de Cálcio/metabolismo , Fibroblastos Associados a Câncer/efeitos dos fármacos , Proteínas do Tecido Nervoso/metabolismo , Próstata/efeitos dos fármacos , Neoplasias da Próstata/tratamento farmacológico , Estilbenos/farmacologia , Canais de Potencial de Receptor Transitório/metabolismo , Sequência de Aminoácidos , Apoptose/efeitos dos fármacos , Cálcio/metabolismo , Canais de Cálcio/análise , Canais de Cálcio/genética , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Linhagem Celular Tumoral , Humanos , Masculino , Mutação , Proteínas do Tecido Nervoso/análise , Proteínas do Tecido Nervoso/genética , Próstata/metabolismo , Próstata/patologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Resveratrol , Canal de Cátion TRPA1 , Canais de Potencial de Receptor Transitório/análise , Canais de Potencial de Receptor Transitório/genética , Microambiente Tumoral/efeitos dos fármacos
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