Deciphering the Role of Ca2+ Signalling in Cancer Metastasis: From the Bench to the Bedside

Alharbi, Abdullah; Zhang, Yuxuan; Parrington, John

doi:10.3390/cancers13020179

Cited by 10 publications

(5 citation statements)

References 154 publications

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“…Therefore, inhibiting P2RY2 in CRC might be either useless or counter-productive in terms of cancer cell survival. However, because Ca 2+ mobilization as well as extracellular ATP exposure and P2RY2 activation have been involved in metastasis, cell cycle progression, cell motility and drug resistance [ 2 , 28 , 40 , 41 , 42 , 73 , 74 , 76 , 77 , 78 , 79 , 80 , 81 , 82 ], it would be interesting to further explore the effects of P2RY2 inhibition on these specific cellular processes associated with cancer progression.…”

Section: Discussionmentioning

confidence: 99%

Expression Pattern of Purinergic Signaling Components in Colorectal Cancer Cells and Differential Cellular Outcomes Induced by Extracellular ATP and Adenosine

Dillard

Borde

Mohammad

et al. 2021

IJMS

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The purine nucleotide adenosine triphosphate (ATP) is known for its fundamental role in cellular bioenergetics. However, in the last decades, different works have described emerging functions for ATP, such as that of a danger signaling molecule acting in the extracellular space on both tumor and stromal compartments. Beside its role in immune cell signaling, several studies have shown that high concentrations of extracellular ATP can directly or indirectly act on cancer cells. Accordingly, it has been reported that purinergic receptors are widely expressed in tumor cells. However, their expression pattern is often associated with contradictory cellular outcomes. In this work, we first investigated gene expression profiles through “RNA-Sequencing” (RNA Seq) technology in four colorectal cancer (CRC) cell lines (HT29, LS513, LS174T, HCT116). Our results demonstrate that CRC cells mostly express the A2B, P2X4, P2Y1, P2Y2 and P2Y11 purinergic receptors. Among these, the P2Y1 and P2Y2 coding genes are markedly overexpressed in all CRC cells compared to the HCEC-1CT normal-like colonic cells. We then explored the cellular outcomes induced by extracellular ATP and adenosine. Our results show that in terms of cell death induction extracellular ATP is consistently more active than adenosine against CRC, while neither compound affected normal-like colonic cell survival. Intriguingly, while for the P2Y2 receptor pharmacological inhibition completely abolished the rise in cytoplasmic Ca2+ observed after ATP exposure in all CRC cell lines, Ca2+ mobilization only impacted the cellular outcome for HT29. In contrast, non-selective phosphodiesterase inhibition completely abolished the effects of extracellular ATP on CRC cells, suggesting that cAMP and/or cGMP levels might determine cellular outcome. Altogether, our study provides novel insights into the characterization of purinergic signaling in CRC.

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Section: Discussionmentioning

confidence: 99%

Expression Pattern of Purinergic Signaling Components in Colorectal Cancer Cells and Differential Cellular Outcomes Induced by Extracellular ATP and Adenosine

Dillard

Borde

Mohammad

et al. 2021

IJMS

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“…Despite a minimal change in apoptosis, it is possible that this increase in calcium could have consequential effects on other cellular processes not directly examined here. Calcium is a well-studied secondary messenger in many oncogenic and metastatic signaling processes, such as migration, invasion, proliferation, and EMT [ 55 ]. In this study, we observed that increased calcium concentrations from Yoda1 and resveratrol correlated with an increased aspect ratio, a hallmark of EMT.…”

Section: Discussionmentioning

confidence: 99%

Piezo1 Mechano-Activation Is Augmented by Resveratrol and Differs between Colorectal Cancer Cells of Primary and Metastatic Origin

et al. 2022

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Cancer cells must survive aberrant fluid shear stress (FSS) in the circulation to metastasize. Herein, we investigate the role that FSS has on colorectal cancer cell apoptosis, proliferation, membrane damage, calcium influx, and therapeutic sensitization. We tested this using SW480 (primary tumor) and SW620 cells (lymph node metastasis) derived from the same patient. The cells were exposed to either shear pulses, modeling millisecond intervals of high FSS seen in regions of turbulent flow, or sustained shear to model average magnitudes experienced by circulating tumor cells. SW480 cells were significantly more sensitive to FSS-induced death than their metastatic counterparts. Shear pulses caused significant cell membrane damage, while constant shear decreased cell proliferation and increased the expression of CD133. To investigate the role of mechanosensitive ion channels, we treated cells with the Piezo1 agonist Yoda1, which increased intracellular calcium. Pretreatment with resveratrol further increased the calcium influx via the lipid-raft colocalization of Piezo1. However, minimal changes in apoptosis were observed due to calcium saturation, as predicted via a computational model of apoptosis. Furthermore, SW480 cells had increased levels of Piezo1, calcium influx, and TRAIL-mediated apoptosis compared to SW620 cells, highlighting differences in the mechano-activation of metastatic cells, which may be a necessary element for successful dissemination in vivo.

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“…It has been well documented that in solid tumors, cancer cells remodel Ca 2+ signaling to enhance cancer hallmarks ( 1 , 2 ). Our review emphasizes that similar alterations occur in blood cancer, driven by changes in expression, function and possibly mutations in the Ca 2+ -toolkit components.…”

Section: Discussionmentioning

confidence: 99%

“…The deregulation of signaling by calcium ions (Ca 2+ ) has been extensively studied in solid tumors ( 1 , 2 ). Changes to Ca 2+ channels and effectors via mutations or changes in expression affect many functional capabilities responsible for cancer growth, invasion, and metastasis ( 2 – 5 ).…”

Section: Introductionmentioning

confidence: 99%

Deregulated calcium signaling in blood cancer: Underlying mechanisms and therapeutic potential

Immanuel

Li²,

Green³

et al. 2022

Front. Oncol.

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Intracellular calcium signaling regulates diverse physiological and pathological processes. In solid tumors, changes to calcium channels and effectors via mutations or changes in expression affect all cancer hallmarks. Such changes often disrupt transport of calcium ions (Ca2+) in the endoplasmic reticulum (ER) or mitochondria, impacting apoptosis. Evidence rapidly accumulates that this is similar in blood cancer. Principles of intracellular Ca2+ signaling are outlined in the introduction. We describe different Ca2+-toolkit components and summarize the unique relationship between extracellular Ca2+ in the endosteal niche and hematopoietic stem cells. The foundational data on Ca2+ homeostasis in red blood cells is discussed, with the demonstration of changes in red blood cell disorders. This leads to the role of Ca2+ in neoplastic erythropoiesis. Then we expand onto the neoplastic impact of deregulated plasma membrane Ca2+ channels, ER Ca2+ channels, Ca2+ pumps and exchangers, as well as Ca2+ sensor and effector proteins across all types of hematologic neoplasms. This includes an overview of genetic variants in the Ca2+-toolkit encoding genes in lymphoid and myeloid cancers as recorded in publically available cancer databases. The data we compiled demonstrate that multiple Ca2+ homeostatic mechanisms and Ca2+ responsive pathways are altered in hematologic cancers. Some of these alterations may have genetic basis but this requires further investigation. Most changes in the Ca2+-toolkit do not appear to define/associate with specific disease entities but may influence disease grade, prognosis, treatment response, and certain complications. Further elucidation of the underlying mechanisms may lead to novel treatments, with the aim to tailor drugs to different patterns of deregulation. To our knowledge this is the first review of its type in the published literature. We hope that the evidence we compiled increases awareness of the calcium signaling deregulation in hematologic neoplasms and triggers more clinical studies to help advance this field.

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Deciphering the Role of Ca2+ Signalling in Cancer Metastasis: From the Bench to the Bedside

Cited by 10 publications

References 154 publications

Expression Pattern of Purinergic Signaling Components in Colorectal Cancer Cells and Differential Cellular Outcomes Induced by Extracellular ATP and Adenosine

Expression Pattern of Purinergic Signaling Components in Colorectal Cancer Cells and Differential Cellular Outcomes Induced by Extracellular ATP and Adenosine

Piezo1 Mechano-Activation Is Augmented by Resveratrol and Differs between Colorectal Cancer Cells of Primary and Metastatic Origin

Deregulated calcium signaling in blood cancer: Underlying mechanisms and therapeutic potential

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