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Intracellular Calcium Levels and Cell Fate in Cancer: Interplay between Senescence, Autophagy and Apoptosis

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 September 2020) | Viewed by 27878

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Special Issue Editors

Dr. Amantini Consuelo

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Guest Editor

School of Bioscience and Biotechnology, University of Camerino, 62032 Camerino, Italy
Interests: TRP; cancer biology; apoptosis; autophagy; senescence; circulating stem cell; chemoresistance
Special Issues, Collections and Topics in MDPI journals

Dr. Valerio Farfariello

E-Mail Website
Guest Editor

Laboratoire de Physiologie Cellulaire - INSERM U1003, Université de Lille - Faculté des Sciences et Technologies, 59655 Villeneuve d’Ascq CEDEX, France
Interests: TRP channels; cell death; senescence; calcium homeostasis

Dr. Maria Beatrice Morelli

E-Mail Website
Guest Editor

School of Pharmacy, University of Camerino, 62032 Camerino, Italy
Interests: glioblastoma; TRP channel; mucolipins; autophagy; overall survival; transient receptor potential channels; tumor progression; chemotherapy resistance;cancer biology; cancer stem cell; circulating tumor cell; liquid biopsy; biomarkers; ion channel; natural compound; cannabinoids
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Intracellular calcium ion (Ca²⁺) levels play a pivotal role in the control of cell proliferation, differentiation, migration and death. The disruption of Ca²⁺ homeostasis has been shown to contribute to the development of malignant phenotypes. In this regard, a relevant role for non-selective cation-permeable channels localized in the plasma membrane, endoplasmic reticulum, mitochondria and lysosomes, has been clarified. Mutations, aberrant expression or changes in the cellular localization of ion channels have been associated with tumors through the modulation of cancer cell growth, metastatic ability, stemness, and acquisition of chemoresistance.

Cell fate choice is crucial for the acquisition of malignant phenotypes, and related to this, autophagy, senescence, and apoptosis seem to be interconnected in cancer development, playing roles in tumor initiation, progression, and response to anticancer therapies.

This Special Issue will present an overview of the latest research regarding tumor dependence on calcium-mediated autophagy, senescence, and apoptosis. We invite authors to submit original papers and reviews related to the roles played by cation channels in these three processes or in their cross-regulation in cancer, their involvement in carcinogenesis, as well as the discovery of new promising drug targets.

Dr. Consuelo Amantini
Dr. Valerio Farfariello
Dr. Maria Beatrice Morelli
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

cation channels
cancer
autophagy
senescence
apoptosis
calcium dysregulation
targeted therapy

Published Papers (4 papers)

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Research

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11 pages, 3167 KiB

Open AccessArticle

Combined Poziotinib with Manidipine Treatment Suppresses Ovarian Cancer Stem-Cell Proliferation and Stemness

by Heejin Lee, Jun Woo Kim, Dong-Seok Lee and Sang-Hyun Min

Int. J. Mol. Sci. 2020, 21(19), 7379; https://doi.org/10.3390/ijms21197379 - 6 Oct 2020

Cited by 10 | Viewed by 2976

Abstract

Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy in women worldwide, with an overall 5 year survival rate below 30%. The low survival rate is associated with the persistence of cancer stem cells (CSCs) after chemotherapy. Therefore, CSC-targeting strategies are required for successful EOC treatment. Pan-human epidermal growth factor receptor 4 (HER4) and L-type calcium channels are highly expressed in ovarian CSCs, and treatment with the pan-HER inhibitor poziotinib or calcium channel blockers (CCBs) selectively inhibits the growth of ovarian CSCs via distinct molecular mechanisms. In this study, we tested the hypothesis that combination treatment with poziotinib and CCBs can synergistically inhibit the growth of ovarian CSCs. Combined treatment with poziotinib and manidipine (an L-type CCB) synergistically suppressed ovarian CSC sphere formation and viability compared with either drug alone. Moreover, combination treatment synergistically reduced the expression of stemness markers, including CD133, KLF4, and NANOG, and stemness-related signaling molecules, such as phospho-STAT5, phospho-AKT, phospho-ERK, and Wnt/β-catenin. Moreover, poziotinib with manidipine dramatically induced apoptosis in ovarian CSCs. Our results suggest that the combinatorial use of poziotinib with a CCB can effectively inhibit ovarian CSC survival and function. Full article

(This article belongs to the Special Issue Intracellular Calcium Levels and Cell Fate in Cancer: Interplay between Senescence, Autophagy and Apoptosis)

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21 pages, 5346 KiB

Open AccessArticle

Mechanistic Study of Triazole Based Aminodiol Derivatives in Leukemic Cells—Crosstalk between Mitochondrial Stress-Involved Apoptosis and Autophagy

by She-Hung Chan, Wohn-Jenn Leu, Sharada Prasanna Swain, Jui-Ling Hsu, Duen-Ren Hou and Jih-Hwa Guh

Int. J. Mol. Sci. 2020, 21(7), 2470; https://doi.org/10.3390/ijms21072470 - 2 Apr 2020

Cited by 3 | Viewed by 3579

Abstract

Various derivatives that mimic ceramide structures by introducing a triazole to connect the aminodiol moiety and long alkyl chain have been synthesized and screened for their anti-leukemia activity. SPS8 stood out among the derivatives, showing cytotoxic selectivity between leukemic cell lines and human peripheral blood mononuclear cells (about ten times). DAPI nuclear staining and H&E staining revealed DNA fragmentation under the action of SPS8. SPS8 induced an increase in intracellular Ca²⁺ levels and mitochondrial stress in HL-60 cells identified by the loss of mitochondrial membrane potential, transmission electron microscopy (TEM) examination, and altered expressions of Bcl-2 family proteins. SPS8 also induced autophagy through the detection of Atg5, beclin-1, and LC3 II protein expression, as well as TEM examination. Chloroquine, an autophagy inhibitor, promoted SPS8-induced apoptosis, suggesting the cytoprotective role of autophagy in hindering SPS8 from apoptosis. Furthermore, SPS8 was shown to alter the expressions of a variety of genes using a microarray analysis and volcano plot filtering. A further cellular signaling pathways analysis suggested that SPS8 induced several cellular processes in HL-60, including the sterol biosynthesis process and cholesterol biosynthesis process, and inhibited some cellular pathways, in which STAT3 was the most critical nuclear factor. Further identification revealed that SPS8 inhibited the phosphorylation of STAT3, representing the loss of cytoprotective activity. In conclusion, the data suggest that SPS8 induces both apoptosis and autophagy in leukemic cells, in which autophagy plays a cytoprotective role in impeding apoptosis. Moreover, the inhibition of STAT3 phosphorylation may support SPS8-induced anti-leukemic activity. Full article

(This article belongs to the Special Issue Intracellular Calcium Levels and Cell Fate in Cancer: Interplay between Senescence, Autophagy and Apoptosis)

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Review

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27 pages, 2048 KiB

Open AccessReview

Various Aspects of Calcium Signaling in the Regulation of Apoptosis, Autophagy, Cell Proliferation, and Cancer

by Simone Patergnani, Alberto Danese, Esmaa Bouhamida, Gianluca Aguiari, Maurizio Previati, Paolo Pinton and Carlotta Giorgi

Int. J. Mol. Sci. 2020, 21(21), 8323; https://doi.org/10.3390/ijms21218323 - 6 Nov 2020

Cited by 164 | Viewed by 12477

Abstract

Calcium (Ca²⁺) is a major second messenger in cells and is essential for the fate and survival of all higher organisms. Different Ca²⁺ channels, pumps, or exchangers regulate variations in the duration and levels of intracellular Ca²⁺, which may be transient or sustained. These changes are then decoded by an elaborate toolkit of Ca²⁺-sensors, which translate Ca²⁺ signal to intracellular operational cell machinery, thereby regulating numerous Ca²⁺-dependent physiological processes. Alterations to Ca²⁺ homoeostasis and signaling are often deleterious and are associated with certain pathological states, including cancer. Altered Ca²⁺ transmission has been implicated in a variety of processes fundamental for the uncontrolled proliferation and invasiveness of tumor cells and other processes important for cancer progression, such as the development of resistance to cancer therapies. Here, we review what is known about Ca²⁺ signaling and how this fundamental second messenger regulates life and death decisions in the context of cancer, with particular attention directed to cell proliferation, apoptosis, and autophagy. We also explore the intersections of Ca²⁺ and the therapeutic targeting of cancer cells, summarizing the therapeutic opportunities for Ca²⁺ signal modulators to improve the effectiveness of current anticancer therapies. Full article

(This article belongs to the Special Issue Intracellular Calcium Levels and Cell Fate in Cancer: Interplay between Senescence, Autophagy and Apoptosis)

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25 pages, 1344 KiB

Open AccessReview

Endoplasmic Reticulum Calcium Pumps and Tumor Cell Differentiation

by Bela Papp, Sophie Launay, Pascal Gélébart, Atousa Arbabian, Agnes Enyedi, Jean-Philippe Brouland, Edgardo D. Carosella and Homa Adle-Biassette

Int. J. Mol. Sci. 2020, 21(9), 3351; https://doi.org/10.3390/ijms21093351 - 9 May 2020

Cited by 14 | Viewed by 8170

Abstract

Endoplasmic reticulum (ER) calcium homeostasis plays an essential role in cellular calcium signaling, intra-ER protein chaperoning and maturation, as well as in the interaction of the ER with other organelles. Calcium is accumulated in the ER by sarco/endoplasmic reticulum calcium ATPases (SERCA enzymes) that generate by active, ATP-dependent transport, a several thousand-fold calcium ion concentration gradient between the cytosol (low nanomolar) and the ER lumen (high micromolar). SERCA enzymes are coded by three genes that by alternative splicing give rise to several isoforms, which can display isoform-specific calcium transport characteristics. SERCA expression levels and isoenzyme composition vary according to cell type, and this constitutes a mechanism whereby ER calcium homeostasis is adapted to the signaling and metabolic needs of the cell, depending on its phenotype, its state of activation and differentiation. As reviewed here, in several normal epithelial cell types including bronchial, mammary, gastric, colonic and choroid plexus epithelium, as well as in mature cells of hematopoietic origin such as pumps are simultaneously expressed, whereas in corresponding tumors and leukemias SERCA3 expression is selectively down-regulated. SERCA3 expression is restored during the pharmacologically induced differentiation of various cancer and leukemia cell types. SERCA3 is a useful marker for the study of cell differentiation, and the loss of SERCA3 expression constitutes a previously unrecognized example of the remodeling of calcium homeostasis in tumors. Full article

(This article belongs to the Special Issue Intracellular Calcium Levels and Cell Fate in Cancer: Interplay between Senescence, Autophagy and Apoptosis)

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