Endolysosomal Ca2+ Signaling in Cancer: The Role of TPC2, From Tumorigenesis to Metastasis.
Ontology highlight
ABSTRACT:
SUBMITTER: Alharbi AF
PROVIDER: S-EPMC6904370 | biostudies-literature | 2019
REPOSITORIES: biostudies-literature
Publications
Endolysosomal Ca<sup>2+</sup> Signaling in Cancer: The Role of TPC2, From Tumorigenesis to Metastasis.
Alharbi Abeer F AF Parrington John J
Frontiers in cell and developmental biology 20191204
Ca<sup>2+</sup> homeostasis is dysregulated in cancer cells and affects processes such as tumorigenesis, angiogenesis, autophagy, progression, and metastasis. Emerging evidence has suggested that endolysosomal cation channels sustain several cancer hallmarks involving proliferation, metastasis, and angiogenesis. Here, we investigate the role of TPC1-2, TRPML1-3, and P2×4 in cancer, with a particular focus on the role of TPC2 in cancer development, melanoma, and other cancer types as well as its ...[more]
Similar Datasets
Project description:During the development of the early spinal circuitry in zebrafish, spontaneous Ca2+ transients in the primary motor neurons (PMNs) are reported to transform from being slow and uncorrelated, to being rapid, synchronized and patterned. In this study, we demonstrated that in intact zebrafish, Ca2+ release via two-pore channel type 2 (TPC2) from acidic stores/endolysosomes is required for the establishment of synchronized activity in the PMNs. Using the SAIGFF213A;UAS:GCaMP7a double-transgenic zebrafish line, Ca2+ transients were visualized in the caudal PMNs (CaPs). TPC2 inhibition via molecular, genetic or pharmacological means attenuated the CaP Ca2+ transients, and decreased the normal ipsilateral correlation and contralateral anti-correlation, indicating a disruption in normal spinal circuitry maturation. Furthermore, treatment with MS-222 resulted in a complete (but reversible) inhibition of the CaP Ca2+ transients, as well as a significant decrease in the concentration of the Ca2+ mobilizing messenger, nicotinic acid adenine diphosphate (NAADP) in whole embryo extract. Together, our new data suggest a novel function for NAADP/TPC2-mediated Ca2+ signaling in the development, coordination, and maturation of the spinal network in zebrafish embryos.
| S-EPMC6669046 | biostudies-literature
Project description:Metastatic cancer is one of the major causes of cancer-related mortalities. Metastasis is a complex, multi-process phenomenon, and a hallmark of cancer. Calcium (Ca2+) is a ubiquitous secondary messenger, and it has become evident that Ca2+ signalling plays a vital role in cancer. Ca2+ homeostasis is dysregulated in physiological processes related to tumour metastasis and progression-including cellular adhesion, epithelial-mesenchymal transition, cell migration, motility, and invasion. In this review, we looked at the role of intracellular and extracellular Ca2+ signalling pathways in processes that contribute to metastasis at the local level and also their effects on cancer metastasis globally, as well as at underlying molecular mechanisms and clinical applications. Spatiotemporal Ca2+ homeostasis, in terms of oscillations or waves, is crucial for hindering tumour progression and metastasis. They are a limited number of clinical trials investigating treating patients with advanced stages of various cancer types. Ca2+ signalling may serve as a novel hallmark of cancer due to the versatility of Ca2+ signals in cells, which suggests that the modulation of specific upstream/downstream targets may be a therapeutic approach to treat cancer, particularly in patients with metastatic cancers.
| S-EPMC7825727 | biostudies-literature
Project description:The activities of organellar ion channels are often regulated by Ca2+ and H+, which are present in high concentrations in many organelles. Here we report a structural element critical for dual Ca2+/pH regulation of TRPML1, a Ca2+-release channel crucial for endolysosomal function. TRPML1 mutations cause mucolipidosis type IV (MLIV), a severe lysosomal storage disorder characterized by neurodegeneration, mental retardation and blindness. We obtained crystal structures of the 213-residue luminal domain of human TRPML1 containing three missense MLIV-causing mutations. This domain forms a tetramer with a highly electronegative central pore formed by a novel luminal pore loop. Cysteine cross-linking and cryo-EM analyses confirmed that this architecture occurs in the full-length channel. Structure-function studies demonstrated that Ca2+ and H+ interact with the luminal pore and exert physiologically important regulation. The MLIV-causing mutations disrupt the luminal-domain structure and cause TRPML1 mislocalization. Our study reveals the structural underpinnings of TRPML1's regulation, assembly and pathogenesis.
| S-EPMC5336481 | biostudies-literature
Project description:Psychiatric disorders are caused by complex and diverse factors, and numerous mechanisms have been proposed for the pathogenesis of these disorders. Accumulating evidence suggests that oxidative stress is one of the general factors involved in the pathogenesis/pathophysiology of major psychiatric disorders, including bipolar disorder, depression, anxiety disorder, and schizophrenia. Indeed, some clinical trials have shown improvement of the symptoms of these disorders by antioxidant supplementation. However, the molecular basis for the relationship between oxidative stress and the pathogenesis of psychiatric disorders remains largely unknown. In general, Ca2+ channels play central roles in neuronal functions, including neuronal excitability, neurotransmitter release, synaptic plasticity, and gene regulation, and genes that encode Ca2+ channels have been found to be associated with psychiatric disorders. Notably, a class of Ca2+-permeable transient receptor potential (TRP) cation channels is activated by changes in cellular redox status, whereby these TRP channels can link oxidative stress to Ca2+ signals. Given the unique characteristic of redox-sensitive TRP channels, these channels could be a target for delineating the pathogenesis or pathophysiology of psychiatric disorders. In this review, we summarize the outcomes of clinical trials for antioxidant treatment in patients with psychiatric disorders and the current insights into the physiological/pathological significance of redox-sensitive TRP channels in the light of neural functions, including behavioral phenotypes, and discuss the potential role of TRP channels in the pathogenesis of psychiatric disorders. Investigation of redox-sensitive TRP channels may lead to the development of novel therapeutic strategies for the treatment of psychiatric disorders.
| S-EPMC7905097 | biostudies-literature
Project description:IntroductionTransmembrane protein 16A (TMEM16A) is a Ca2+-activated chloride channel that plays a role in cancer cell proliferation, migration, invasion, and metastasis. However, whether TMEM16A contributes to breast cancer metastasis remains unknown.ObjectiveIn this study, we investigated whether TMEM16A channel activation by ROCK1/moesin promotes breast cancer metastasis.MethodsWound healing assays and transwell migration and invasion assays were performed to study the migration and invasion of MCF-7 and T47D breast cancer cells. Western blotting was performed to evaluate the protein expression, and whole-cell patch clamp recordings were used to record TMEM16A Cl- currents. A mouse model of breast cancer lung metastasis was generated by injecting MCF-7 cells via the tail vein. Metastatic nodules in the lung were assessed by hematoxylin and eosin staining. Lymph node metastasis, overall survival, and metastasis-free survival of breast cancer patients were assessed using immunohistochemistry and The Cancer Genome Atlas dataset.ResultsTMEM16A activation promoted breast cancer cell migration and invasion in vitro as well as breast cancer metastasis in mice. Patients with breast cancer who had higher TMEM16A levels showed greater lymph node metastasis and shorter survival. Mechanistically, TMEM16A promoted migration and invasion by activating EGFR/STAT3/ROCK1 signaling, and the role of the TMEM16A channel activity was important in this respect. ROCK1 activation by RhoA enhanced the TMEM16A channel activity via the phosphorylation of moesin at T558. The cooperative action of TMEM16A and ROCK1 was supported through clinical findings indicating that breast cancer patients with high levels of TMEM16A/ROCK1 expression showed greater lymph node metastasis and poor survival.ConclusionOur findings revealed a novel mechanism underlying TMEM16A-mediated breast cancer metastasis, in which ROCK1 increased TMEM16A channel activity via moesin phosphorylation and the increase in TMEM16A channel activities promoted cell migration and invasion. TMEM16A inhibition may be a novel strategy for treating breast cancer metastasis.
| S-EPMC8463928 | biostudies-literature
Project description:Recent studies have implicated important roles for endolysosomal ion channels in cancer biology. We used UK Biobank data to characterise the relationships between genetic variants in two genes coding for endolysosomal ion channels-i.e. TPCN2 and P2RX4-and cancer in terms of the definition of tumour types, susceptibility, and prognosis. We investigated these relationships at both global and local levels with regard to specific types of cancer, including malignant neoplasms of the brain, breast, bronchus, lung, colon, lymphoid and haematopoietic systems, skin, ovary, prostate, rectum, thyroid gland, lip, oral cavity, pharynx, and urinary tract. Apart from rs3829241 (p value < 0.05), all the genetic variants were in Hardy-Weinberg equilibrium. We included 468,436 subjects in the analysis and stratified them into two major cohorts: cancer-free controls (385,253) and cancer cases (83,183). For the first time, we report novel associations between genetic variants of TPCN2 and P2RX4 and cancer/cancer subtypes in the UK Biobank's population. Genotype GG in TPCN2 rs3750965 was significantly associated with a decreased risk of cancer and an increased risk of lip, oral cavity, and pharynx cancer and cancer recurrence in patients with prostate cancer, and genotypes GA/GG were associated with a significantly lower risk of developing various malignant neoplasms (involving melanoma, prostate, mesothelial, and soft tissues). rs35264875:TA was associated with a high risk of cancer at the global level, with subtypes of cancer at the local level (including breast, colon, prostate, and stated or presumed primary cancer of lymphoid, haematopoietic, and related tissue), and with a significantly low risk of cancer metastasis. rs72932540:GA was associated with a higher incidence of cancer/cancer subtypes (including breast, melanoma, and rectal cancer), and genotypes GA/GG were associated with an increased risk of prostate cancer. The P2RX4 rs25644 allele GG was associated with a high risk of prostate cancer, whereas it was associated with a low risk of cancer recurrence in patients with prostate cancer. Genotypes GA/GG in rs28360472 were associated with an increased risk of breast, mesothelial, and soft tissue cancers but with a decreased risk of colon cancer. We also provide insights into the pathophysiological contributions made by these significant polymorphisms to cancer/cancer subtypes and their effects on expression or channel activity. Further investigations of these genetic variants could help identify novel cancer biomarkers and facilitate the development of new diagnostic and therapeutic strategies. This would constitute a further step towards personalised cancer care.
| S-EPMC8275681 | biostudies-literature
Project description:Recent studies show that talin2 has a higher affinity to β-integrin tails and is indispensable for traction force generation and cell invasion. However, its roles in cell migration, cancer cell metastasis and tumorigenesis remain to be determined. Here, we used MDA-MB-231 human breast cancer cells as a model to define the roles of talin2 in cell migration, invasion, metastasis and tumorigenesis. We show here that talin2 knockdown (KD) inhibited cell migration and focal adhesion dynamics, a key step in cell migration, and that talin2 knockout (KO) inhibited cell invasion and traction force generation, the latter is crucial for cell invasion. Re-expression of talin2WT in talin2-KO cells restored traction force generation and cell invasion, but that of talin2S339C, a β-integrin-binding deficient mutant, did not. Moreover, talin2 KO (or KD) suppressed tumorigenesis and metastasis in mouse xenograft models. However, surprisingly, re-expression of talin2WT in talin2-KO cells did not rescue tumorigenesis. Thus, talin2 is required for breast cancer cell migration, invasion, metastasis and tumorigenesis, although exogenous expression of high levels of talin2 could inhibit tumorigenesis.
| S-EPMC5739781 | biostudies-literature
Project description:The clinical significance of STIM proteins and Orai Ca2+ channels in tumor progression has been demonstrated in different types of cancers. Podosomes are dynamic actin-rich cellular protrusions that facilitate cancer cell invasiveness by degrading extracellular matrix. Whether STIM1-dependent Ca2+ signaling facilitates cancer cell invasion through affecting podosome formation remains unclear. Here we show that the invasive fronts of cancer tissues overexpress STIM1, accompanied by active store-operated Ca2+ entry (SOCE). Interfering SOCE activity by SOCE inhibitors and STIM1 or Orai1 knockdown remarkably affects podosome rosettes formation. Mechanistically, STIM1-silencing significantly alters the podosome rosettes dynamics, shortens the maintenance phase of podosome rosettes and reduces cell invasiveness. The subsequently transient expression of STIM1 cDNA in STIM1-null (STIM1-/-) mouse embryo fibroblasts rescues the suppression of podosome formation, suggesting that STIM1-mediated SOCE activation directly regulates podosome formation. This study uncovers SOCE-mediated Ca2+ microdomain that is the molecular basis for Ca2+ sensitivity controlling podosome formation.
| S-EPMC5599537 | biostudies-literature
Project description:BackgroundBrain metastases are a major cause of death in patients with metastatic breast cancer. While surgical resection and radiation therapy are effective treatment modalities, the majority of patients will succumb from disease progression. We have developed a novel therapy for brain metastases that delivers athermal radiofrequency electromagnetic fields that are amplitude-modulated at breast cancer specific frequencies (BCF).Methods27.12 MHz amplitude-modulated BCF were administered to a patient with a breast cancer brain metastasis by placing a spoon-shaped antenna on the anterior part of the tongue for three one-hour treatments every day. In preclinical models, a BCF dose, equivalent to that delivered to the patient's brain, was administered to animals implanted with either brain metastasis patient derived xenografts (PDXs) or brain-tropic cell lines. We also examined the efficacy of combining radiation therapy with BCF treatment. Additionally, the mechanistic underpinnings associated with cancer inhibition was identified using an agnostic approach.FindingsAnimal studies demonstrated a significant decrease in growth and metastases of brain-tropic cell lines. Moreover, BCF treatment of PDXs established from patients with brain metastases showed strong suppression of their growth ability. Importantly, BCF treatment led to significant and durable regression of brain metastasis of a patient with triple negative breast cancer. The tumour inhibitory effect was mediated by Ca2+ influx in cancer cells through CACNA1H T-type voltage-gated calcium channels, which, acting as the cellular antenna for BCF, activated CAMKII/p38 MAPK signalling and inhibited cancer stem cells through suppression of β-catenin/HMGA2 signalling. Furthermore, BCF treatment downregulated exosomal miR-1246 level, which in turn decreased angiogenesis in brain environment. Therefore, targeted growth inhibition of breast cancer metastases was achieved through CACNA1H.InterpretationWe demonstrate that BCF, as a single agent or in combination with radiation, is a novel treatment approach to the treatment of brain metastases. This paradigm shifting modality warrants further clinical trials for this unmet medical need.
| S-EPMC6604768 | biostudies-literature
Project description:Primary cilia are chemosensors that play a dual role to either activate or repress Hedgehog signaling, depending on presence or absence of ligand, respectively. While inhibition of ciliogenesis has been shown to be characteristic of breast cancers, the functional consequence is unknown. Here, for the first time, inhibition of ciliogenesis led to earlier tumor formation, faster tumor growth rate, higher grade tumor formation, and increased metastasis in the polyoma middle T (PyMT) mouse model of breast cancer. In in vitro model systems, inhibition of ciliogenesis resulted in increased expression of Hedgehog-target genes through a mechanism involving loss of the repressor form of the GLI transcription factor (GLIR) and activation of Hedgehog target gene expression through cross-talk with TGF-alpha (TGFA) signaling. Bioinformatics analysis revealed that increased Hedgehog signaling is frequently associated with increased TGFA; signaling in patients with triple-negative breast cancers (TNBC), a particularly aggressive breast cancer subtype. These results identify a previously unrecognized role for inhibition of ciliogenesis in breast cancer progression. This study identifies inhibition of ciliogenesis as an important event for activation of Hedgehog signaling and progression of breast cancer to a more aggressive, metastatic disease.Implications: These findings change the way we understand how cancer cells turn on a critical signaling pathways and a provide rationale for developing novel therapeutic approaches to target noncanonical Hedgehog signaling for the treatment of breast cancer. Mol Cancer Res; 15(10); 1421-30. ©2017 AACR.
| S-EPMC7478142 | biostudies-literature