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Biomedicines
Special Issues
Calcium Signaling and Its Dysregulation in Cancer
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Calcium Signaling and Its Dysregulation in Cancer

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cancer Biology and Oncology".

Deadline for manuscript submissions: closed (15 July 2022) | Viewed by 17365

Special Issue Editor

Dr. Randolph C. Elble

E-Mail Website
Guest Editor
Department of Pharmacology, Southern Illinois University School of Medicine, Springfield, IL 62794, USA
Interests: epithelial differentiation processes in breast, oral, and lung cancers; metastasis mechanisms; cell junctional signaling; EGFR, Her2, and E-cadherin in anoikis; role of intracellular calcium stores in proliferation, differentiation, and cell death; p53, cell stress, and DNA damage response; cell senescence; CLCA gene family
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

There is a growing appreciation of the role that intracellular calcium plays in both tumor suppression and progression. Calcium is the common currency of differentiation and homeostasis. It is stored primarily in the endoplasmic reticulum, rationed according to need, and replenished from the extracellular milieu via store-operated calcium entry (SOCE). This currency is disbursed by the inositol triphosphate (IP3) receptor in response to diverse extracellular signals. The rate of release is governed by regulators of metabolism and proliferation, differentiation, autophagy, survival, and programmed cell death, with different outcomes depending on the strength of the signal and context. This system is fundamentally tumor-suppressive, and cancer cells must find ways to subvert it in order to exploit its growth-promoting effects.

This Special Issue invites both original manuscripts describing novel findings and cutting-edge review articles illustrating the many mechanisms by which cancer cells dysregulate SOCE, IP3 and ryanodine receptors, calcium transfer to mitochondria, and signaling to downstream effectors and targets to prevent cell death and enhance metabolism, mitogenesis, and metastasis.

Prof. Dr. Randolph C. Elble
Guest Editor

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). 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

  • intracellular calcium
  • IP3R
  • SOCE
  • RyR
  • STIM
  • ORAI

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Published Papers (4 papers)

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Research

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13 pages, 17235 KiB  
Article
Altered Calcium Influx Pathways in Cancer-Associated Fibroblasts
by Francisco Sadras, Teneale A. Stewart, Mélanie Robitaille, Amelia A. Peters, Priyakshi Kalita-de Croft, Patsy S. Soon, Jodi M. Saunus, Sunil R. Lakhani, Sarah J. Roberts-Thomson and Gregory R. Monteith
Biomedicines 2021, 9(6), 680; https://doi.org/10.3390/biomedicines9060680 - 16 Jun 2021
Cited by 6 | Viewed by 3290
Abstract
Cancer-associated fibroblasts (CAFs) represent an important component of the tumour microenvironment and are implicated in disease progression. Two outstanding questions in cancer biology are how CAFs arise and how they might be targeted therapeutically. The calcium signal also has an important role in [...] Read more.
Cancer-associated fibroblasts (CAFs) represent an important component of the tumour microenvironment and are implicated in disease progression. Two outstanding questions in cancer biology are how CAFs arise and how they might be targeted therapeutically. The calcium signal also has an important role in tumorigenesis. To date, the role of calcium signalling pathways in the induction of the CAF phenotype remains unexplored. A CAF model was generated through exogenous transforming growth factor beta 1 (TGFβ1) stimulation of the normal human mammary fibroblast cell line, HMF3S (HMF3S-CAF), and changes in calcium signalling were investigated. Functional changes in HMF3S-CAF calcium signalling pathways were assessed using a fluorescent indicator, gene expression, gene-silencing and pharmacological approaches. HMF3S-CAF cells demonstrated functionally altered calcium influx pathways with reduced store-operated calcium entry. In support of a calcium signalling switch, two voltage-gated calcium channel (VGCC) family members, CaV1.2 and CaV3.2, were upregulated in HMF3S-CAFs and a subset of patient-derived breast CAFs. Both siRNA-mediated silencing and pharmacological inhibition of CaV1.2 or CaV3.2 significantly impaired CAF activation in HMF3S cells. Our findings show that VGCCs contribute to TGFβ1-mediated induction of HMF3S-CAF cells and both transcriptional interference and pharmacological antagonism of CaV1.2 and CaV3.2 inhibit CAF induction. This suggests a potential therapeutic role for targeting calcium signalling in breast CAFs. Full article
(This article belongs to the Special Issue Calcium Signaling and Its Dysregulation in Cancer)
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16 pages, 16015 KiB  
Article
A Novel Biomarker Driving Poor-Prognosis Liver Cancer: Overexpression of the Mitochondrial Calcium Gatekeepers
by Chia-Jung Li, Hung-Yu Lin, Chih-Jan Ko, Ji-Ching Lai and Pei-Yi Chu
Biomedicines 2020, 8(11), 451; https://doi.org/10.3390/biomedicines8110451 - 24 Oct 2020
Cited by 24 | Viewed by 3078
Abstract
Several studies have indicated the biological role of mitochondrial Ca2+ uptake in cancer pathophysiology; however, its implications in predicting the prognosis of hepatocellular carcinoma (HCC) are not yet fully understood. Here, we collected tumor specimens and adjacent normal liver tissues from 354 [...] Read more.
Several studies have indicated the biological role of mitochondrial Ca2+ uptake in cancer pathophysiology; however, its implications in predicting the prognosis of hepatocellular carcinoma (HCC) are not yet fully understood. Here, we collected tumor specimens and adjacent normal liver tissues from 354 confirmed HCC patients and analyzed the levels of cyclic adenosine monophosphate (cAMP) responsive element binding protein 1 (CREB), mitochondrial calcium uniporter (MCU), mitochondrial calcium uptake 1 and 2 (MICU1, MICU2) using bioinformatics, qRT-PCR, and immunohistochemistry (IHC), and their relationship with clinicopathological characteristics and prognosis. HCC patients with low CREB/MICU1 and high MCU/MICU2 expression exhibited poor survival rate and prognosis in overall survival (OS) and disease-free survival (DFS) analyses. Low CREB/MICU1 and low MICU1 alone indicated poor prognosis in stage I/II and III/IV patients, respectively. In the poor differentiation/undifferentiation group, low expression of MICU1 indicated poor clinical outcomes. Low CREB/MICU1 expression suggested poor outcomes in patients with or without hepatitis B virus (HBV) infection and poor prognosis in the HCV infection group. In the non- hepatitis C virus (HCV) infection group, low MCU1 indicated a poor prognosis. Multivariate analysis demonstrated that CREB and MICU1 expression showed prognostic significance. This study demonstrates the prognostic significance of CREB, MCU, MICU1, and MICU2, in predicting HCC outcomes. Low CREB/MICU1 and high MCU/MICU2 in HCC tissues are associated with poor prognosis, thus offering a novel perspective in the clinical management for HCC patients. Full article
(This article belongs to the Special Issue Calcium Signaling and Its Dysregulation in Cancer)
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Review

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59 pages, 7010 KiB  
Review
Advances in Intracellular Calcium Signaling Reveal Untapped Targets for Cancer Therapy
by Aarushi Sharma, Grace T. Ramena and Randolph C. Elble
Biomedicines 2021, 9(9), 1077; https://doi.org/10.3390/biomedicines9091077 - 24 Aug 2021
Cited by 15 | Viewed by 5275
Abstract
Intracellular Ca2+ distribution is a tightly regulated process. Numerous Ca2+ chelating, storage, and transport mechanisms are required to maintain normal cellular physiology. Ca2+-binding proteins, mainly calmodulin and calbindins, sequester free intracellular Ca2+ ions and apportion or transport them [...] Read more.
Intracellular Ca2+ distribution is a tightly regulated process. Numerous Ca2+ chelating, storage, and transport mechanisms are required to maintain normal cellular physiology. Ca2+-binding proteins, mainly calmodulin and calbindins, sequester free intracellular Ca2+ ions and apportion or transport them to signaling hubs needing the cations. Ca2+ channels, ATP-driven pumps, and exchangers assist the binding proteins in transferring the ions to and from appropriate cellular compartments. Some, such as the endoplasmic reticulum, mitochondria, and lysosomes, act as Ca2+ repositories. Cellular Ca2+ homeostasis is inefficient without the active contribution of these organelles. Moreover, certain key cellular processes also rely on inter-organellar Ca2+ signaling. This review attempts to encapsulate the structure, function, and regulation of major intracellular Ca2+ buffers, sensors, channels, and signaling molecules before highlighting how cancer cells manipulate them to survive and thrive. The spotlight is then shifted to the slow pace of translating such research findings into anticancer therapeutics. We use the PubMed database to highlight current clinical studies that target intracellular Ca2+ signaling. Drug repurposing and improving the delivery of small molecule therapeutics are further discussed as promising strategies for speeding therapeutic development in this area. Full article
(This article belongs to the Special Issue Calcium Signaling and Its Dysregulation in Cancer)
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22 pages, 1414 KiB  
Review
From Orai to E-Cadherin: Subversion of Calcium Trafficking in Cancer to Drive Proliferation, Anoikis-Resistance, and Metastasis
by Aarushi Sharma and Randolph C. Elble
Biomedicines 2020, 8(6), 169; https://doi.org/10.3390/biomedicines8060169 - 21 Jun 2020
Cited by 12 | Viewed by 4904
Abstract
The common currency of epithelial differentiation and homeostasis is calcium, stored primarily in the endoplasmic reticulum, rationed according to need, and replenished from the extracellular milieu via store-operated calcium entry (SOCE). This currency is disbursed by the IP3 receptor in response to diverse [...] Read more.
The common currency of epithelial differentiation and homeostasis is calcium, stored primarily in the endoplasmic reticulum, rationed according to need, and replenished from the extracellular milieu via store-operated calcium entry (SOCE). This currency is disbursed by the IP3 receptor in response to diverse extracellular signals. The rate of release is governed by regulators of proliferation, autophagy, survival, and programmed cell death, the strength of the signal leading to different outcomes. Intracellular calcium acts chiefly through intermediates such as calmodulin that regulates growth factor receptors such as epidermal growth factor receptor (EGFR), actin polymerization, and adherens junction assembly and maintenance. Here we review this machinery and its role in differentiation, then consider how cancer cells subvert it to license proliferation, resist anoikis, and enable metastasis, either by modulating the level of intracellular calcium or its downstream targets or effectors such as EGFR, E-cadherin, IQGAP1, TMEM16A, CLCA2, and TRPA1. Implications are considered for the roles of E-cadherin and growth factor receptors in circulating tumor cells and metastasis. The discovery of novel, cell type-specific modulators and effectors of calcium signaling offers new possibilities for cancer chemotherapy. Full article
(This article belongs to the Special Issue Calcium Signaling and Its Dysregulation in Cancer)
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