BBA - Molecular Cell Research (v.1863, #6PB)

Calcium and Cell Fate by Thierry Capiod; Jacques Haiech; Claus W. Heizmann; Joachim Krebs; Olivier Mignen (1335-1336).

The calcium-signaling toolkit: Updates needed by Charlotte Dubois; Natalia Prevarskaya; Fabien Vanden Abeele (1337-1343).
Here, we review the role of Ca2 + in apoptosis, namely that ER Ca2 + depletion or a sustained elevation of cytosolic or mitochondrial Ca2 + concentration are sufficient to trigger apoptosis. These concepts have emerged by the use of ER stressor agents that decrease the ER Ca2 + pool by inhibiting SERCA pumps. However, aside from their well-known actions on Ca2 + homeostasis disruption leading to apoptosis, new evidence show that some ER Ca2 + modulators have significant implications in other Ca2 +-mediated or Ca2 +-independent pathways determining cell fate suggesting a more complex regulation of apoptosis by intracellular Ca2 +. Here, we discuss the crucial interplay between Ca2 + mediated apoptosis, the Unfold Protein Response and autophagy determining cell fate, and the molecular compounds that have been used to depict these pathways. This review of the literature clearly shows the need for new inhibitors that do not interfere concomitantly with autophagy and Ca2 + signaling. This article is part of a Special Issue entitled: Calcium and Cell Fate. Guest Editors: Jacques Haiech, Claus Heizmann, Joachim Krebs, Thierry Capiod and Olivier Mignen.
Keywords: Calcium; Apoptosis; Unfold Protein Response; Autophagy; SERCA; Inhibitor;

Calcium-ATPases: Gene disorders and dysregulation in cancer by Donna Dang; Rajini Rao (1344-1350).
Ca2 +-ATPases belonging to the superfamily of P-type pumps play an important role in maintaining low, nanomolar cytoplasmic Ca2 + levels at rest and priming organellar stores, including the endoplasmic reticulum, Golgi, and secretory vesicles with high levels of Ca2 + for a wide range of signaling functions. In this review, we introduce the distinct subtypes of Ca2 +-ATPases and their isoforms and splice variants and provide an overview of their specific cellular roles as they relate to genetic disorders and cancer, with a particular emphasis on recent findings on the secretory pathway Ca2 +-ATPases (SPCA). Mutations in human ATP2A2, ATP2C1 genes, encoding housekeeping isoforms of the endoplasmic reticulum (SERCA2) and secretory pathway (SPCA1) pumps, respectively, confer autosomal dominant disorders of the skin, whereas mutations in other isoforms underlie various muscular, neurological, or developmental disorders. Emerging evidence points to an important function of dysregulated Ca2 +-ATPase expression in cancers of the colon, lung, and breast where they may serve as markers of differentiation or novel targets for therapeutic intervention. We review the mechanisms underlying the link between calcium homeostasis and cancer and discuss the potential clinical relevance of these observations. This article is part of a Special Issue entitled: Calcium and Cell Fate. Guest Editors: Jacques Haiech, Claus Heizmann, Joachim Krebs, Thierry Capiod and Olivier Mignen.
Keywords: Calcium ATPase; Calcium signaling; Secretory pathway; Lactation; Breast cancer; Golgi;

Multifaceted plasma membrane Ca2 + pumps: From structure to intracellular Ca2 + handling and cancer by Rita Padányi; Katalin Pászty; Luca Hegedűs; Karolina Varga; Béla Papp; John T. Penniston; Ágnes Enyedi (1351-1363).
Plasma membrane Ca2 + ATPases (PMCAs) are intimately involved in the control of intracellular Ca2 + concentration. They reduce Ca2 + in the cytosol not only by direct ejection, but also by controlling the formation of inositol-1,4,5-trisphosphate and decreasing Ca2 + release from the endoplasmic reticulum Ca2 + pool. In mammals four genes (PMCA1–4) are expressed, and alternative RNA splicing generates more than twenty variants. The variants differ in their regulatory characteristics. They localize into highly specialized membrane compartments and respond to the incoming Ca2 + with distinct temporal resolution. The expression pattern of variants depends on cell type; a change in this pattern can result in perturbed Ca2 + homeostasis and thus altered cell function. Indeed, PMCAs undergo remarkable changes in their expression pattern during tumorigenesis that might significantly contribute to the unbalanced Ca2 + homeostasis of cancer cells. This article is part of a Special Issue entitled: Calcium and Cell Fate . Guest Editors: Jacques Haiech, Claus Heizmann, Joachim Krebs, Thierry Capiod and Olivier Mignen.
Keywords: Plasma membrane Ca2 + ATPase; Ca2 +-calmodulin; Phosphatidylinositol-4,5-bisphosphate binding; Ca2 + signaling; Differentiation; Tumor progression;

ER functions of oncogenes and tumor suppressors: Modulators of intracellular Ca2 + signaling by Mart Bittremieux; Jan B. Parys; Paolo Pinton; Geert Bultynck (1364-1378).
Intracellular Ca2 + signals that arise from the endoplasmic reticulum (ER), the major intracellular Ca2 +-storage organelle, impact several mitochondrial functions and dictate cell survival and cell death processes. Furthermore, alterations in Ca2 + signaling in cancer cells promote survival and establish a high tolerance towards cell stress and damage, so that the on-going oncogenic stress does not result in the activation of cell death. Over the last years, the mechanisms underlying these oncogenic alterations in Ca2 + signaling have started to emerge. An important aspect of this is the identification of several major oncogenes, including Bcl-2, Bcl-XL, Mcl-1, PKB/Akt, and Ras, and tumor suppressors, such as p53, PTEN, PML, BRCA1, and Beclin 1, as direct and critical regulators of Ca2 +-transport systems located at the ER membranes, including IP3 receptors and SERCA Ca2 + pumps. In this way, these proteins execute part of their function by controlling the ER-mitochondrial Ca2 + fluxes, favoring either survival (oncogenes) or cell death (tumor suppressors). Oncogenic mutations, gene deletions or amplifications alter the expression and/or function of these proteins, thereby changing the delicate balance between oncogenes and tumor suppressors, impacting oncogenesis and favoring malignant cell function and behavior. In this review, we provided an integrated overview of the impact of the major oncogenes and tumor suppressors, often altered in cancer cells, on Ca2 + signaling from the ER Ca2 + stores. This article is part of a Special Issue entitled: Calcium and Cell Fate. Guest Editors: Jacques Haiech, Claus Heizmann, Joachim Krebs, Thierry Capiod and Olivier Mignen.
Keywords: Tumor suppressors; Oncogenes; Calcium; Cancer; Cell death; Endoplasmic reticulum;

Nicotinic acid adenine dinucleotide phosphate (NAADP) is a Ca2 + mobilizing second messenger that belongs to the superfamily of regulatory adenine nucleotides. Though NAADP has been known since 20 years, several aspects of its metabolism and molecular mode of action are still under discussion. Though the importance of the type 1 ryanodine receptor was discovered and published already in 2002 Hohenegger et al. (2002 Oct 15) , recent data re-emphasize these original findings in pancreatic acinar cells and in T-lymphocytes.Here we review recent developments in NAADP formation and metabolism, putative target Ca2 + channels for NAADP with special emphasis on the type 1 ryanodine receptor, and NAADP binding proteins. The latter are basis for a unifying hypothesis for NAADP action. Finally, the role of NAADP in T cell Ca2 + signaling and activation is discussed. This article is part of a Special Issue entitled: Calcium and Cell Fate . Guest Editors: Jacques Haiech, Claus Heizmann, Joachim Krebs, Thierry Capiod and Olivier Mignen.Display Omitted
Keywords: NAADP; Ryanodine receptor; T cell; Signal transduction;

Pharmacological targeting of ion channels for cancer therapy: In vivo evidences by Luigi Leanza; Antonella Managò; Mario Zoratti; Erich Gulbins; Ildiko Szabo (1385-1397).
Since the discovery of the participation of various ion channels in the regulation of cell proliferation and programmed cell death two decades ago, the field exploring ion channel function in relation to cancer has undergone rapid development. Although the mechanisms accounting for the impact of ion channel modulators on cancer growth have not been fully clarified in all cases, numerous in vivo experiments targeting diverse ion channels in various cancer models illustrate the great potentiality of this approach and promote ion channels to the class of oncological targets. In the present review we give an updated overview of the field and critically discuss the promising results obtained in pre-clinical models using specific pharmacological modulators of calcium, sodium, potassium and anion-permeable ion channels, whose expression is often altered in tumor cells and tissues. The most, especially critical issues are specificity of action and side-effects. Interestingly, some of the most potent drugs are natural products, and several of the active compounds are already used in the clinic for other purposes. In these latter cases involving drug repositioning we may expect a faster progression from preclinical to clinical studies. This article is part of a Special Issue entitled: Calcium and Cell Fate. Guest Editors: Jacques Haiech, Claus Heizmann, Joachim Krebs, Thierry Capiod and Olivier Mignen.
Keywords: Calcium-permeable channels; Potassium channels; Sodium channels; Anion channels; In vivo cancer models; Pharmacological targeting;

The calcium-sensing receptor and the hallmarks of cancer by Samawansha Tennakoon; Abhishek Aggarwal; Enikö Kállay (1398-1407).
The calcium-sensing receptor (CaSR) plays a pivotal role in systemic calcium metabolism by regulating parathyroid hormone secretion and urinary calcium excretion. The CaSR is ubiquitously expressed, implying a wide range of functions regulated by this receptor. Abnormal CaSR function affects the development of both calciotropic disorders such as hyperparathyroidism, and non-calciotropic disorders such as cardiovascular disease and cancer, which are the leading causes of mortality worldwide.The CaSR is able to bind a plethora of ligands; it interacts with multiple G protein subtypes, and regulates highly divergent downstream signalling pathways, depending on the cellular context. The CaSR is a key regulator for such diverse processes as hormone secretion, gene expression, inflammation, proliferation, differentiation, and apoptosis. Due to this pleiotropy, the CaSR is able to regulate cell fate and is implicated in the development of many types of benign or malignant tumours of the breast, prostate, parathyroid, and colon. In cancer, the CaSR appears to have paradoxical roles, and depending on the tissue involved, it is able to prevent or promote tumour growth. In tissues like the parathyroid or colon, the CaSR inhibits proliferation and induces terminal differentiation of the cells. Therefore, loss of the receptor, as seen in colorectal or parathyroid tumours, confers malignant potential, suggestive of a tumour suppressor role. In contrast, in prostate and breast tumours the expression of the CaSR is increased and it seems that it favours metastasis to the bone, acting as an oncogene.Deciphering the molecular mechanism driving the CaSR in the different tissues could lead to development of new allosteric drug compounds that selectively target the CaSR and have therapeutic potential for cancer. This article is part of a Special Issue entitled: Calcium and Cell Fate . Guest Editors: Jacques Haiech, Claus Heizmann, Joachim Krebs, Thierry Capiod and Olivier Mignen.Display Omitted
Keywords: Cancer; Calcium; G protein-coupled receptors; Biased signalling; Oncogene; Tumour suppressor;

Advances in next-generation sequencing allow very comprehensive analyses of large numbers of cancer genomes leading to an increasingly better characterization and classification of cancers. Comparing genomic data predicts candidate genes driving development, growth, or metastasis of cancer. Cancer driver genes are defined as genes whose mutations are causally implicated in oncogenesis whereas passenger mutations are defined as not being oncogenic. Currently, a list of several hundred cancer driver mutations is discussed including prominent members like TP53, BRAF, NRAS, or NF1. According to the vast literature on Ca2 + and cancer, Ca2 + signals and the underlying Ca2 + channels and transporters certainly influence the development, growth, and metastasis of many cancers. In this review, I focus on the calcium release-activated calcium (CRAC) channel genes STIM and Orai and their role for cancer development, growth, and metastasis. STIM and Orai genes are being discussed in the context of current cancer concepts with a focus on the driver-passenger hypothesis. One result of this discussion is the hypothesis that a driver analysis of Ca2 + homeostasis-related genes should not be carried out by looking at isolated genes. Rather a pool of “Ca2 + genes” might be considered to act as one potential cancer driver. This article is part of a Special Issue entitled: Calcium and Cell Fate . Guest Editors: Jacques Haiech, Claus Heizmann, Joachim Krebs, Thierry Capiod and Olivier Mignen.
Keywords: CRAC channels; Calcium; STIM; STIM1; STIM2; Orai; Orai1; Orai2; Orai3; TRPV5; TRPV6; Cancer; Tumor; Cancer driver gene; Cancer passenger gene; CTLA4; Checkpoint therapy; Cytotoxic T lymphocytes (CTL); Natural killer (NK) cells; Tumor microenvironment;

STIM and calcium channel complexes in cancer by Isaac Jardin; Juan A. Rosado (1418-1426).
The ion Ca2+ is a ubiquitous second messenger that mediates a variety of cellular functions. Dysfunction of the mechanisms involved in Ca2+ homeostasis underlies a number of pathological processes, including cancer. Store-operated Ca2+ entry (SOCE) is a major mechanism for Ca2+ entry modulated by the intracellular Ca2+ stores. The Ca2 +-selective store-operated current (I CRAC) is mediated by the endoplasmic reticulum (ER) Ca2+ sensor STIM1 and the store-operated Ca2+ (SOC) channel Orai1, while other non-selective cation currents (I SOC) involves the participation of members of the canonical transient receptor potential (TRPC) channel family, including TRPC1. Distinct isoforms of the key components of SOCE have been described in mammalian cells, STIM1 and 2, Orai1-3 and TRPC1-7. In cancer cells, SOCE has been reported to play an important role in cell cycle progression and proliferation, migration, metastasis and evasion of apoptosis. Changes in the expression of the key elements of SOCE and Ca2+ homeostasis remodeling have been account to play important roles in the phenotypic changes observed in transformed cells. Despite there are differences in the expression level of the molecular components of SOCE, as well as in the relevance of the STIM, Orai and TRPC isoforms in SOCE and tumorigenesis among cancer cell types, there is a body of evidence supporting an important role for SOCE underlying the phenotypic modifications of cancer cells that propose STIM and the SOC channels as suitable candidate targets for future prognostic or therapeutic strategies. This article is part of a Special Issue entitled: Calcium and Cell Fate. Guest Editors: Jacques Haiech, Claus Heizmann, Joachim Krebs, Thierry Capiod and Olivier Mignen.
Keywords: STIM1; STIM2; TRP channels; Orai; Tumorigenesis; Cancer cells;

The store-operated Ca2 + entry-mediated signaling is important for cancer spread by Yih-Fung Chen; Keng-Fu Hsu; Meng-Ru Shen (1427-1435).
Tumor cell migration and invasion are essential steps in the metastatic cascade that has great impact on patient outcomes. Spatial and temporal organization of Ca2 + signaling regulates the multiple aspects of migration machinery, including cytoskeletal reorganization, traction force generation, and focal adhesion dynamics. Stromal interaction molecules (STIM) and Orai proteins, recently identified as critical constituents of store-operated Ca2 + entry (SOCE), have been implicated in cancer cell migration and tumor metastasis. The clinical significance of STIM proteins and Orai Ca2 + channels in tumor progression and their diagnostic and prognostic potentials have also been demonstrated in different types of cancers. Here we review the recent advances in understanding the important roles and regulatory mechanisms of STIM/Orai-mediated SOCE in cancer spread. The clinical implications and the emergence as a selective target for cancer therapeutics are also discussed. This article is part of a Special Issue entitled: Calcium and Cell Fate. Guest Editors: Jacques Haiech, Claus Heizmann, Joachim Krebs, Thierry Capiod and Olivier Mignen.
Keywords: Stromal interaction molecule (STIM); Orai; Store-operated Ca2 + entry (SOCE); Migration; Invasion; Metastasis;

Beyond ion-conduction: Channel-dependent and -independent roles of TRP channels during development and tissue homeostasis by Kirsten S. Vrenken; Kees Jalink; Frank N. van Leeuwen; Jeroen Middelbeek (1436-1446).
Transient receptor potential (TRP) channels comprise a family of cation channels implicated in a variety of cellular processes, including proliferation, cell migration and cell survival. As a consequence, members of this ion family play prominent roles during embryonic development, tissue maintenance and cancer progression. Although most TRP channels are non-selective, many cellular responses, mediated by TRP channels, appear to be calcium-dependent. In addition, there is mounting evidence for channel-independent roles for TRP channels. In this review, we will discuss how both these channel-dependent and -independent mechanisms affect cellular programs essential during embryonic development, and how perturbations in these pathways contribute to a variety of pathologies. This article is part of a Special Issue entitled: Calcium and Cell Fate. Guest Editors: Jacques Haiech, Claus Heizmann, Joachim Krebs, Thierry Capiod and Olivier Mignen.
Keywords: TRP channels; Calcium; Embryonic development; Epithelial-mesenchymal transition (EMT); Tissue homeostasis;

Calcium signaling orchestrates glioblastoma development: Facts and conjunctures by Catherine Leclerc; Jacques Haeich; Francisco J. Aulestia; Marie-Claude Kilhoffer; Andrew L. Miller; Isabelle Néant; Sarah E. Webb; Etienne Schaeffer; Marie-Pierre Junier; Hervé Chneiweiss; Marc Moreau (1447-1459).
While it is a relatively rare disease, glioblastoma multiform (GBM) is one of the more deadly adult cancers. Following current interventions, the tumor is never eliminated whatever the treatment performed; whether it is radiotherapy, chemotherapy, or surgery. One hypothesis to explain this poor outcome is the “cancer stem cell” hypothesis. This concept proposes that a minority of cells within the tumor mass share many of the properties of adult neural stem cells and it is these that are responsible for the growth of the tumor and its resistance to existing therapies. Accumulating evidence suggests that Ca2 + might also be an important positive regulator of tumorigenesis in GBM, in processes involving quiescence, maintenance, proliferation, or migration. Glioblastoma tumors are generally thought to develop by co-opting pathways that are involved in the formation of an organ. We propose that the cells initiating the tumor, and subsequently the cells of the tumor mass, must hijack the different checkpoints that evolution has selected in order to prevent the pathological development of an organ. In this article, two main points are discussed. (i) The first is the establishment of a so-called “cellular society,” which is required to create a favorable microenvironment. (ii) The second is that GBM can be considered to be an organism, which fights to survive and develop. Since GBM evolves in a limited space, its only chance of development is to overcome the evolutionary checkpoints. For example, the deregulation of the normal Ca2 + signaling elements contributes to the progression of the disease. Thus, by manipulating the Ca2 + signaling, the GBM cells might not be killed, but might be reprogrammed toward a new fate that is either easy to cure or that has no aberrant functioning. This article is part of a Special Issue entitled: Calcium and Cell Fate . Guest Editors: Jacques Haiech, Claus Heizmann, Joachim Krebs, Thierry Capiod and Olivier Mignen.Display Omitted
Keywords: Glioblastoma; Calcium signaling; Cancer stem cells; Cell competition; Quiescence; Proliferation; Migration; Inflammation;