Role of the calcium toolkit in cancer stem cells

Terrié, Elodie; Coronas, Valérie; Constantin, Bruno

doi:10.1016/j.ceca.2019.05.001

Cited by 34 publications

(31 citation statements)

References 137 publications

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“…Autophagy is a self‐digestion process of the cells developed for degradation and recycling of proteins, damaged organelles, and lipids, thereby acting as a control mechanism of cellular homeostasis. Notably, it is generally accepted that autophagy represents a promising approach to counteract CSCs aggressiveness [21] and that this role of autophagy is connected with Ca 2+ ‐dependent signaling pathways [22] . However, contradictory roles of Ca 2+ in the process of autophagy have been proposed [21,23] .…”

Section: Resultsmentioning

confidence: 99%

A Cyclometalated Ir^III Complex Conjugated to a Coumarin Derivative Is a Potent Photodynamic Agent against Prostate Differentiated and Tumorigenic Cancer Stem Cells

Novohradský

Marková

Kostrhunová

et al. 2021

Chemistry A European J

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A cyclometalated IrIII complex conjugated to a far‐red‐emitting coumarin, IrIII‐COUPY (3), was recently shown as a very promising photosensitizer suitable for photodynamic therapy of cancer. Therefore, the primary goal of this work was to deepen knowledge on the mechanism of its photoactivated antitumor action so that this information could be used to propose a new class of compounds as drug candidates for curing very hardly treatable human tumors, such as androgen resistant prostatic tumors of metastatic origin. Conventional anticancer chemotherapies exhibit several disadvantages, such as limited efficiency to target cancer stem cells (CSCs), which are considered the main reason for chemotherapy resistance, relapse, and metastasis. Herein, we show, using DU145 tumor cells, taken as the model of hormone‐refractory and aggressive prostate cancer cells resistant to conventional antineoplastic drugs, that the photoactivated conjugate 3 very efficiently eliminates both prostate bulk (differentiated) and prostate hardly treatable CSCs simultaneously and with a similar efficiency. Notably, the very low toxicity of IrIII‐COUPY conjugate in the prostate DU145 cells in the dark and its pronounced selectivity for tumor cells compared with noncancerous cells could result in low side effects and reduced damage of healthy cells during the photoactivated therapy by this agent. Moreover, the experiments performed with the 3D spheroids formed from DU145 CSCs showed that conjugate 3 can penetrate the inner layers of tumor spheres, which might markedly increase its therapeutic effect. Also interestingly, this conjugate induces apoptotic cell death in prostate cancer DU145 cells associated with calcium signaling flux in these cells and autophagy. To the best of our knowledge, this is the first study demonstrating that a photoactivatable metal‐based compound is an efficient agent capable of killing even hardly treatable CSCs.

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Section: Resultsmentioning

confidence: 99%

A Cyclometalated Ir^III Complex Conjugated to a Coumarin Derivative Is a Potent Photodynamic Agent against Prostate Differentiated and Tumorigenic Cancer Stem Cells

Novohradský

Marková

Kostrhunová

et al. 2021

Chemistry A European J

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“…We found that NCX2 levels are negatively correlated with intracellular Ca 2+ concentrations. Intracellular Ca 2+ is a second messenger involved in regulating various cellular processes, including cell proliferation and apoptosis in cancer [21,34]. It has been reported that the concentration of intracellular Ca 2+ is higher in the osteosarcoma cell line MG-63 than the normal osteoblast line hFOB1.…”

Section: Discussionmentioning

confidence: 99%

The MiR-193a-5p/NCX2/AKT Axis Promotes Invasion and Metastasis of Osteosarcoma

Chen

Ning

Zeng³

et al. 2021

Preprint

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MiR-193a-5p has been observed to have oncogenic or tumor suppressive functions in different kinds of cancers, but its role and molecular mechanism in osteosarcoma are elusive. Na+/Ca2+ exchangers (NCX1, NCX2 and NCX3) normally extrude Ca2+ from the cell, and deregulation of the intracellular Ca2+ homeostasis is related to several kinds of diseases, including cancer. The present study demonstrated that miR-193a-5p was upregulated in osteosarcoma tissues compared with the corresponding adjacent noncancerous tissues, and promoted colony formation, migration, invasion and epithelial-mesenchymal transition (EMT) in osteosarcoma cells (SaOS-2 and U-2OS), as well as metastasis in a murine xenograft model. Tandem mass tag-based quantitative proteomics analysis identified NCX2 as a potential target of miR-193a-5p. Luciferase activity assays and Western blotting further confirmed that miR-193a-5p recognized the 3′-untranslated region of NCX2 mRNA, and negatively regulated NCX2 expression. NCX2 was downregulated in osteosarcoma tissues, and its expression was negatively correlated with miR-193a-5p levels. Ectopic expression of NCX2 in osteosarcoma cells could reverse the oncogenicity of miR-193a-5p, indicating that miR-193a-5p exerted its effects by targeting NCX2. Further study demonstrated that NCX2 suppresses Ca2+-dependent Akt phosphorylation by decreasing intracellular Ca2+ concentration, then inhibited EMT process. Treatment with the antagomir against miR-193a-5p sensitized osteosarcoma to the Akt inhibitor afuresertib in a murine xenograft model. In conclusion, a miR-193a-5p/NCX2/AKT signaling axis contributes to the progression of osteosarcoma, which may provide a new therapeutic target for osteosarcoma treatment.

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“…We found that NCX2 levels are negatively correlated with intracellular Ca 2+ concentrations. Intracellular Ca 2+ is a second messenger involved in regulating various cellular processes, including cell proliferation and apoptosis in cancer [19,34]. It has been reported that the concentration of intracellular Ca 2+ is higher in the osteosarcoma cell line MG-63 than the normal osteoblast line hFOB1.…”

Section: Discussionmentioning

confidence: 99%

The MiR-193a-5p/NCX2/AKT Axis Promotes Invasion and Metastasis of Osteosarcoma

Chen

Ning

Zeng³

et al. 2021

Preprint

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Background: MiR-193a-5p has been observed to have oncogenic or tumor-suppressive function in different kinds of cancers. Na+/Ca2+ exchangers (NCX1, NCX2 and NCX3) normally extrude Ca2+ from the cell, and deregulation of the intracellular Ca2+ homeostasis is related to several kinds of diseases, including cancer. However, their roles and molecular mechanism in osteosarcoma are elusive.Methods: The expression of miR-193a-5p and NCX2 in osteosarcoma and corresponding adjacent noncancerous tissues was investigated by qRT-PCR. Colony formation assay, wound healing assay, transwell invasion assay and xenograft mouse model were used for in vitro and in vivo functional analyses. Tandem mass tag-based quantitative proteomics analysis was performed to identify the targets of miR-193a-5p.Results: This study showed that miR-193a-5p was upregulated in osteosarcoma tissues compared with the corresponding adjacent noncancerous tissues, and promoted colony formation, migration, invasion, and epithelial-mesenchymal transition (EMT) in vitro, as well as metastasis in vivo. Quantitative proteomics analysis identified NCX2 as a potential target of miR-193a-5p. Luciferase activity assay and Western blotting further confirmed that miR-193a-5p recognized the 3′-untranslated region of NCX2 mRNA, and negatively regulated NCX2 expression. NCX2 was downregulated in osteosarcoma tissues, and its expression was negatively correlated with miR-193a-5p levels. Ectopic expression of NCX2 in osteosarcoma cells could counteract the oncogenic effects of miR-193a-5p. These results indicate that miR-193a-5p exerts its effects by targeting NCX2. Further study demonstrated that NCX2 suppressed Ca2+-dependent Akt phosphorylation by decreasing intracellular Ca2+ efflux, then inhibited EMT process. Treatment with the antagomir against miR-193a-5p sensitized osteosarcoma to the Akt inhibitor afuresertib in a murine xenograft tumor model. Conclusion: This study revealed a miR-193a-5p/NCX2/AKT signaling axis in the progression of osteosarcoma, which may provide a new therapeutic target for osteosarcoma treatment.

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Role of the calcium toolkit in cancer stem cells

Cited by 34 publications

References 137 publications

A Cyclometalated Ir^III Complex Conjugated to a Coumarin Derivative Is a Potent Photodynamic Agent against Prostate Differentiated and Tumorigenic Cancer Stem Cells

A Cyclometalated Ir^III Complex Conjugated to a Coumarin Derivative Is a Potent Photodynamic Agent against Prostate Differentiated and Tumorigenic Cancer Stem Cells

The MiR-193a-5p/NCX2/AKT Axis Promotes Invasion and Metastasis of Osteosarcoma

The MiR-193a-5p/NCX2/AKT Axis Promotes Invasion and Metastasis of Osteosarcoma

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Role of the calcium toolkit in cancer stem cells

Cited by 34 publications

References 137 publications

A Cyclometalated IrIII Complex Conjugated to a Coumarin Derivative Is a Potent Photodynamic Agent against Prostate Differentiated and Tumorigenic Cancer Stem Cells

A Cyclometalated IrIII Complex Conjugated to a Coumarin Derivative Is a Potent Photodynamic Agent against Prostate Differentiated and Tumorigenic Cancer Stem Cells

The MiR-193a-5p/NCX2/AKT Axis Promotes Invasion and Metastasis of Osteosarcoma

The MiR-193a-5p/NCX2/AKT Axis Promotes Invasion and Metastasis of Osteosarcoma

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A Cyclometalated Ir^III Complex Conjugated to a Coumarin Derivative Is a Potent Photodynamic Agent against Prostate Differentiated and Tumorigenic Cancer Stem Cells

A Cyclometalated Ir^III Complex Conjugated to a Coumarin Derivative Is a Potent Photodynamic Agent against Prostate Differentiated and Tumorigenic Cancer Stem Cells