Cardiomyocyte proliferation stops at birth when the heart is no longer exposed to maternal blood and, likewise, to regulatory T cells (Tregs) that are expanded to promote maternal tolerance towards ...the fetus. Here, we report a role of Tregs in promoting cardiomyocyte proliferation. Treg-conditioned medium promotes cardiomyocyte proliferation, similar to the serum from pregnant animals. Proliferative cardiomyocytes are detected in the heart of pregnant mothers, and Treg depletion during pregnancy decreases both maternal and fetal cardiomyocyte proliferation. Treg depletion after myocardial infarction results in depressed cardiac function, massive inflammation, and scarce collagen deposition. In contrast, Treg injection reduces infarct size, preserves contractility, and increases the number of proliferating cardiomyocytes. The overexpression of six factors secreted by Tregs (Cst7, Tnfsf11, Il33, Fgl2, Matn2, and Igf2) reproduces the therapeutic effect. In conclusion, Tregs promote fetal and maternal cardiomyocyte proliferation in a paracrine manner and improve the outcome of myocardial infarction.
The Graphical Abstract indicates the Hallmarks of Cancer and their relationship with a cell signalling module involving store operated Ca2+ entry (SOCE) based on STIM/Orai and InsP3 dependent Ca2+ ...release from the ER (via InsP3Rs; IICR). We propose that SOCE/IICR is dynamically modulated to meet the needs of the cell as it transitions through the various stages of oncogenic transformation. In turn, SOCE/IICR influences the physiology of the cell according to the transformation stage.
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•Ca2+ signalling pathways control cellular life and death decisions.•Ca2+ signalling is remodelled and contributes to oncogenic transformation.•Ca2+ release via ER InsP3R channels is remodelled in transformed cells.•STIM/ORAI-mediated store operated Ca2+ entry is altered in cancer•ER Ca2+ release and store operated Ca2+ entry synergise to determine cell fate.
Ca2+ is a pleiotropic messenger that controls life and death decisions from fertilisation until death. Cellular Ca2+ handling mechanisms show plasticity and are remodelled throughout life to meet the changing needs of the cell. In turn, as the demands on a cell alter, for example through a change in its niche environment or its functional requirements, Ca2+ handling systems may be targeted to sustain the remodelled cellular state. Nowhere is this more apparent than in cancer. Oncogenic transformation is a multi-stage process during which normal cells become progressively differentiated towards a cancerous state that is principally associated with enhanced proliferation and avoidance of death. Ca2+ signalling is intimately involved in almost all aspects of the life of a transformed cell and alterations in Ca2+ handling have been observed in cancer. Moreover, this remodelling of Ca2+ signalling pathways is also required in some cases to sustain the transformed phenotype. As such, Ca2+ handling is hijacked by oncogenic processes to deliver and maintain the transformed phenotype. Central to generation of intracellular Ca2+ signals is the release of Ca2+ from the endoplasmic reticulum intracellular (ER) Ca2+ store via inositol 1,4,5-trisphosphate receptors (InsP3Rs). Upon depletion of ER Ca2+, store-operated Ca2+ entry (SOCE) across the plasma membrane occurs via STIM-gated Orai channels. SOCE serves to both replenish stores but also sustain Ca2+ signalling events. Here, we will discuss the role and regulation of these two signalling pathways and their interplay in oncogenic transformation.
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•Oncogenic KRAS suppresses SOCE/ICRAC in colorectal cancer cell (CRC) lines.•STIM expression is remodelled in CRCs following oncogenic KRAS deletion.•STIM1 re-expression is sufficient ...to rescue SOCE in CRCs.•STIM1 expression is regulated by the MEK/ERK pathway in CRCs.
The KRAS GTPase plays a fundamental role in transducing signals from plasma membrane growth factor receptors to downstream signalling pathways controlling cell proliferation, survival and migration. Activating KRAS mutations are found in 20% of all cancers and in up to 40% of colorectal cancers, where they contribute to dysregulation of cell processes underlying oncogenic transformation. Multiple KRAS-regulated cell functions are also influenced by changes in intracellular Ca2+ levels that are concurrently modified by receptor signalling pathways. Suppression of intracellular Ca2+ release mechanisms can confer a survival advantage in cancer cells, and changes in Ca2+ entry across the plasma membrane modulate cell migration and proliferation. However, inconsistent remodelling of Ca2+ influx and its signalling role has been reported in studies of transformed cells. To isolate the interaction between altered Ca2+ handling and mutated KRAS in colorectal cancer, we have previously employed isogenic cell line pairs, differing by the presence of an oncogenic KRAS allele (encoding KRASG13D), and have shown that reduced Ca2+ release from the ER and mitochondrial Ca2+ uptake contributes to the survival advantage conferred by oncogenic KRAS. Here we show in the same cell lines, that Store-Operated Ca2+ Entry (SOCE) and its underlying current, ICRAC are under the influence of KRASG13D. Specifically, deletion of the oncogenic KRAS allele resulted in enhanced STIM1 expression and greater Ca2+ influx. Consistent with the role of KRAS in the activation of the ERK pathway, MEK inhibition in cells with KRASG13D resulted in increased STIM1 expression. Further, ectopic expression of STIM1 in HCT 116 cells (which express KRASG13D) rescued SOCE, demonstrating a fundamental role of STIM1 in suppression of Ca2+ entry downstream of KRASG13D. These results add to the understanding of how ERK controls cancer cell physiology and highlight STIM1 as an important biomarker in cancerogenesis.
The KRAS GTPase plays a fundamental role in transducing signals from plasma membrane growth factor receptors to downstream signalling pathways controlling cell proliferation, survival and migration. ...Activating KRAS mutations are found in 20% of all cancers and in up to 40% of colorectal cancers, where they contribute to dysregulation of cell processes underlying oncogenic transformation. Multiple KRAS-regulated cell functions are also influenced by changes in intracellular Ca
levels that are concurrently modified by receptor signalling pathways. Suppression of intracellular Ca
release mechanisms can confer a survival advantage in cancer cells, and changes in Ca
entry across the plasma membrane modulate cell migration and proliferation. However, inconsistent remodelling of Ca
influx and its signalling role has been reported in studies of transformed cells. To isolate the interaction between altered Ca
handling and mutated KRAS in colorectal cancer, we have previously employed isogenic cell line pairs, differing by the presence of an oncogenic KRAS allele (encoding KRAS
), and have shown that reduced Ca
release from the ER and mitochondrial Ca
uptake contributes to the survival advantage conferred by oncogenic KRAS. Here we show in the same cell lines, that Store-Operated Ca
Entry (SOCE) and its underlying current, I
are under the influence of KRAS
. Specifically, deletion of the oncogenic KRAS allele resulted in enhanced STIM1 expression and greater Ca
influx. Consistent with the role of KRAS in the activation of the ERK pathway, MEK inhibition in cells with KRAS
resulted in increased STIM1 expression. Further, ectopic expression of STIM1 in HCT 116 cells (which express KRAS
) rescued SOCE, demonstrating a fundamental role of STIM1 in suppression of Ca
entry downstream of KRAS
. These results add to the understanding of how ERK controls cancer cell physiology and highlight STIM1 as an important biomarker in cancerogenesis.
Ca
is a pleiotropic messenger that controls life and death decisions from fertilisation until death. Cellular Ca
handling mechanisms show plasticity and are remodelled throughout life to meet the ...changing needs of the cell. In turn, as the demands on a cell alter, for example through a change in its niche environment or its functional requirements, Ca
handling systems may be targeted to sustain the remodelled cellular state. Nowhere is this more apparent than in cancer. Oncogenic transformation is a multi-stage process during which normal cells become progressively differentiated towards a cancerous state that is principally associated with enhanced proliferation and avoidance of death. Ca
signalling is intimately involved in almost all aspects of the life of a transformed cell and alterations in Ca
handling have been observed in cancer. Moreover, this remodelling of Ca
signalling pathways is also required in some cases to sustain the transformed phenotype. As such, Ca
handling is hijacked by oncogenic processes to deliver and maintain the transformed phenotype. Central to generation of intracellular Ca
signals is the release of Ca
from the endoplasmic reticulum intracellular (ER) Ca
store via inositol 1,4,5-trisphosphate receptors (InsP
Rs). Upon depletion of ER Ca
, store-operated Ca
entry (SOCE) across the plasma membrane occurs via STIM-gated Orai channels. SOCE serves to both replenish stores but also sustain Ca
signalling events. Here, we will discuss the role and regulation of these two signalling pathways and their interplay in oncogenic transformation.
The GTPase Ras is a molecular switch engaged downstream of G-protein-coupled receptors and receptor tyrosine kinases that controls multiple cell-fate-determining signalling pathways. Ras signalling ...is frequently deregulated in cancer, underlying associated changes in cell phenotype. Although Ca(2+) signalling pathways control some overlapping functions with Ras, and altered Ca(2+) signalling pathways are emerging as important players in oncogenic transformation, how Ca(2+) signalling is remodelled during transformation and whether it has a causal role remains unclear. We have investigated Ca(2+) signalling in two human colorectal cancer cell lines and their isogenic derivatives in which the allele encoding oncogenic K-Ras (G13D) was deleted by homologous recombination. We show that agonist-induced Ca(2+) release from the endoplasmic reticulum (ER) intracellular Ca(2+) stores is enhanced by loss of K-Ras(G13D) through an increase in the Ca(2+) content of the ER store and a modification of the abundance of inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) subtypes. Consistently, uptake of Ca(2+) into mitochondria and sensitivity to apoptosis was enhanced as a result of K-Ras(G13D) loss. These results suggest that suppression of Ca(2+) signalling is a common response to naturally occurring levels of K-Ras(G13D), and that this contributes to a survival advantage during oncogenic transformation.
ABSTRACT
There is little information available concerning the link between the ryanodine (RY) receptors and the downstream Ca2+ signaling events in β‐cells. In fura‐2 loaded INS‐1E cells, activation ...of RY receptors by 9‐methyl 5,7‐dibromoeudistomin D (MBED) caused a rapid rise of Ca2+i followed by a plateau and repetitive Ca2+i spikes on the plateau. The Ca2+i plateau was abolished by omission of extracellular Ca2+ and by SKF 96365. In the presence of SKF 96365, MBED produced a transient increase of Ca2+i, which was abolished by thapsigargin. Activation of RY receptors caused Ca2+ entry even when the ER Ca2+ pool was depleted by thapsigargin. The Ca2+i plateau was not inhibited by nimodipine or ruthenium red, but was inhibited by membrane depolarization, La3+, Gd3+, niflumic acid, and 2‐aminoethoxydiphenyl borate, agents that inhibit the transient receptor potential channels. The Ca2+i spikes were inhibited by nimodipine and ryanodine, indicating that they were due to Ca2+ influx through the voltage‐gated Ca2+ channels and Ca2+‐induced Ca2+ release (CICR). Activation of RY receptors depolarized membrane potential as measured by patch clamp. Thus, activation of RY receptors leads to coherent changes in Ca2+ signaling, which includes activation of TRP‐like channels, membrane depolarization, activation of the voltage‐gated Ca2+ channels and CICR.
Pancreatic β-cells have ryanodine receptors but little is known about their physiological regulation. Previous studies have shown that arachidonic acid releases Ca
2+ from intracellular stores in ...β-cells but the identity of the channels involved in the Ca
2+ release has not been elucidated. We studied the mechanism by which arachidonic acid induces Ca
2+ concentration changes in pancreatic β-cells. Cytosolic free Ca
2+ concentration was measured in fura-2-loaded INS-1E cells and in primary β-cells from Wistar rats. The increase of cytosolic Ca
2+ concentration induced by arachidonic acid (150
μM) was due to both Ca
2+ release from intracellular stores and influx of Ca
2+ from extracellular medium. 5,8,11,14-Eicosatetraynoic acid, a non-metabolizable analogue of arachidonic acid, mimicked the effect of arachidonic acid, indicating that arachidonic acid itself mediated Ca
2+ increase. The Ca
2+ release induced by arachidonic acid was from the endoplasmic reticulum since it was blocked by thapsigargin. 2-Aminoethyl diphenylborinate (50
μM), which is known to inhibit 1,4,5-inositol-triphosphate-receptors, did not block Ca
2+ release by arachidonic acid. However, ryanodine (100
μM), a blocker of ryanodine receptors, abolished the effect of arachidonic acid on Ca
2+ release in both types of cells. These observations indicate that arachidonic acid is a physiological activator of ryanodine receptors in β-cells.
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