Calcium signaling and cell cycle: Progression or death

Humeau, Juliette; Pedro, José Manuel Bravo-San; Vitale, Ilio; Núñez, Lucía González; Alonso, Carlos; Kroemer, Guido; Senovilla, Laura

doi:10.1016/j.ceca.2017.07.006

Cited by 158 publications

(111 citation statements)

References 214 publications

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“…It has been indicated that intracellular Ca 2+ overload is able to trigger apoptosis. 10 Ca 2+ overload causes mitochondrial cytochrome C leakage and cleaved Caspase 3 that eventually lead to cell apoptosis, which is consistent with our study. Mammalian cellular membranes are highly permeable to water.…”

Section: Discussionsupporting

confidence: 92%

“…First, disruption of intracellular Ca 2+ homeostasis can result in the induction of mitochondrial-mediated apoptosis through the release of cytochrome C, which may contribute to cell death. 10 Therefore, we examined if combination treatment of digoxin and NaCl could induce cytochrome C release from the mitochondria. Protein fraction and western blotting results indicated that the combination dramatically induced the release of cytochrome C from mitochondrial compartment to cytoplasm ( Figure 6A).…”

Section: Digoxin Treatment Combined With Nacl Supplement Dramaticallymentioning

confidence: 99%

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Sodium chloride (NaCl) potentiates digoxin-induced anti-tumor activity in small cell lung cancer

Deng

Shen

Wang

et al. 2018

Cancer Biology & Therapy

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Small cell lung cancer (SCLC) is a malignant neuroendocrine tumor with very high mortality. Effective new therapy for advanced SCLC patients is urgently needed. By screening a FDA-approved drug library, we identified a cardiac glycoside (CG), namely digoxin (an inhibitor of cellular Na/K ATPase pump), which was highly effective in inhibiting SCLC cell growth. Intriguing findings showed that NaCl supplement markedly enhanced the anti-tumor activities of digoxin in both in vitro and in vivo models of SCLC. Subsequent analysis revealed that this novel combination of digoxin/NaCl caused an up-regulation of intracellular Na and Ca levels with an induction of higher resting membrane potential of SCLC cells. We also found that this combination lead to morphological shrinking of SCLC cells, together with high levels of cytochrome C release. Lastly, our data revealed that NaCl supplement was able to induce the expression of ATP1A1 (a Na/K ATPase subunit), in which contributes directly to the increased sensitivity of SCLC cells to digoxin. Thus, this is the first demonstration that NaCl is a potent supplement necessitating superior anti-cancer effects of digoxin for SCLC. Further, our study suggests that digoxin treatment could need to be combined with NaCl supplement in future clinical trial of SCLC, particularly where low Na is often present in SCLC patients.

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Section: Discussionsupporting

confidence: 92%

Section: Digoxin Treatment Combined With Nacl Supplement Dramaticallymentioning

confidence: 99%

Sodium chloride (NaCl) potentiates digoxin-induced anti-tumor activity in small cell lung cancer

Deng

Shen

Wang

et al. 2018

Cancer Biology & Therapy

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“…Ca 2+ ‐mediated signalling plays an important role during cell cycle progression, with oscillating concentrations during G1/S (accompanying DNA replication), and G2/M transition, further proposed to regulate centrosome duplication and segregation, respectively . The activation of calmodulin (CaM), CaM kinases (CaMKs), MAPKs, calcineurin and protein kinase C (PKC) by [Ca 2+ ] i , in turn, activates several transcription factors (eg, nuclear factor of activated T cells (NFAT), activator protein‐1 (AP‐1), nuclear factor κ‐light‐chain‐enhancer of activated B cells (NFκB), cAMP response element‐binding protein (CREB) and c‐Myc), regulating the expression of cyclins and CDKs driving cell cycle progression . NHE‐dependent intracellular alkalinization (a 0.2‐0.3 unit increase in pH i compared to steady‐state pH i of ~7.1) can increase [Ca 2+ ] i under

{HCO}_{3}^{-}

‐free conditions, and alkalinization of pH i (~0.4 pH unit above resting pH i ) can stimulate Ca 2+ release from intracellular stores .…”

Section: Signalling Mechanisms Linking Ph To Cell Proliferationmentioning

confidence: 99%

Roles of pH in control of cell proliferation

2018

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Precise spatiotemporal regulation of intracellular pH (pH ) is a prerequisite for normal cell function, and changes in pH or pericellular pH (pH ) exert important signalling functions. It is well established that proliferation of mammalian cells is dependent on a permissive pH in the slightly alkaline range (7.0-7.2). It is also clear that mitogen signalling in nominal absence of HCO3- is associated with an intracellular alkalinization (~0.3 pH unit above steady-state pH ), which is secondary to activation of Na /H exchange. However, it remains controversial whether this increase in pH is part of the mitogenic signal cascade leading to cell cycle entry and progression, and whether it is relevant under physiological conditions. Furthermore, essentially all studies of pH in mammalian cell proliferation have focused on the mitogen-induced G0-G1 transition, and the regulation and roles of pH during the cell cycle remain poorly understood. The aim of this review is to summarize and critically discuss the possible roles of pH and pH in cell cycle progression. While the focus is on the mammalian cell cycle, important insights from studies in lower eukaryotes are also discussed. We summarize current evidence of links between cell cycle progression and pH and discuss possible pH - and pH sensors and signalling pathways relevant to mammalian proliferation control. The possibility that changes in pH during cell cycle progression may be an integral part of the checkpoint control machinery is explored. Finally, we discuss the relevance of links between pH and proliferation in the context of the perturbed pH homoeostasis and acidic microenvironment of solid tumours.

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“…Notably, via Ca 2+ overload, mitochondrial damage and ER stress are among the best-described pathological factors activating the NLRP3 inflammasome pathway. Extracellular Ca 2+ may enter the cell trough plasma membrane-resident ca 2+ channels called acid-sensing ion channels (ASIcs) (89,90). The calcium-sensing receptor (cASR) has also been reported to increase the concentration of intracellular ca 2+ , initiate the phospholipase C pathway via the intracellular side and induce assembly of the NLRP3 inflammasome complex (91).…”

Section: Activation Of the Nlrp3 Inflammasome Pathway In Ischemic Strokementioning

confidence: 99%

Evidence and perspective for the role of the NLRP3 inflammasome signaling pathway in ischemic stroke and its therapeutic potential (Review)

Liu

Zhang

et al. 2018

Int J Mol Med

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Calcium signaling and cell cycle: Progression or death

Cited by 158 publications

References 214 publications

Sodium chloride (NaCl) potentiates digoxin-induced anti-tumor activity in small cell lung cancer

Sodium chloride (NaCl) potentiates digoxin-induced anti-tumor activity in small cell lung cancer

Roles of pH in control of cell proliferation

Evidence and perspective for the role of the NLRP3 inflammasome signaling pathway in ischemic stroke and its therapeutic potential (Review)

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