Oncogenic K-Ras suppresses IP3-dependent Ca2+ release through remodeling of IP3Rs isoform composition and ER luminal Ca2+ levels in colorectal cancer cell lines

Pierro, Cristina; Cook, Simon J.; Foets, Thomas; Bootman, Martin D.; Roderick, H. Llewelyn

doi:10.1242/jcs.141408

Cited by 69 publications

(65 citation statements)

References 116 publications

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“…This may also result in protein degradation. Similarly, in cells expressing mutant K-Ras, decreased IP 3 R3 and SERCA2b protein expression were observed [350], suggesting an overall dampening of the ER-mitochondrial Ca 2+ transfer through oncogenic inhibition that may provide anti-apoptotic benefits to cancer cells. The tumor suppressor p53 was recently shown to initiate cell death in response to cytotoxic agent Adriamycin, ROS and ER stress, by directly interacting with SERCA at MAMs, and activating SERCA to increase ER Ca 2+ uptake [351, 352].…”

Section: Redox Regulation Of Er and Mitochondrial Ca2+ Modulatorsmentioning

confidence: 99%

Crosstalk between calcium and reactive oxygen species signaling in cancer

2017

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The interplay between Ca2+ and reactive oxygen species (ROS) signaling pathways is well established, with reciprocal regulation occurring at a number of subcellular locations. Many Ca2+ channels at the cell surface and intracellular organelles, including the endoplasmic reticulum and mitochondria are regulated by redox modifications. In turn, Ca2+ signaling can influence the cellular generation of ROS, from sources such as NADPH oxidases and mitochondria. This relationship has been explored in great depth during the process of apoptosis, where surges of Ca2+ and ROS are important mediators of cell death. More recently, coordinated and localized Ca2+ and ROS transients appear to play a major role in a vast variety of pro-survival signaling pathways that may be crucial for both physiological and pathophysiological functions. While much work is required to firmly establish this Ca2+-ROS relationship in cancer, existing evidence from other disease models suggests this crosstalk is likely of significant importance in tumorigenesis. In this review, we describe the regulation of Ca2+ channels and transporters by oxidants and discuss the potential consequences of the ROS-Ca2+ interplay in tumor cells.

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Section: Redox Regulation Of Er and Mitochondrial Ca2+ Modulatorsmentioning

confidence: 99%

Crosstalk between calcium and reactive oxygen species signaling in cancer

2017

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“…In many cases, different mechanisms can be simultaneously operative. For instance, oncogenic KRAS mutations appear to switch the expression from IP 3 R3 into IP 3 R1 and to lower the ER Ca 2+ -store content, together suppressing agonist-induced Ca 2+ release and mitochondrial Ca 2+ accumulation and thus protecting cells against menadione exposure [166]. AKT/PKB phosphorylates all three IP 3 R isoforms, thereby suppressing their pro-apoptotic Ca 2+ -release function [84, 156].…”

Section: The Role Of Ip3r2 In Cell Death and In Senescencementioning

confidence: 99%

The type 2 inositol 1,4,5-trisphosphate receptor, emerging functions for an intriguing Ca2+-release channel

Vervloessem

Yule

Bultynck

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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The inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) type 2 (IP3R2) is an intracellular Ca2+-release channel located on the endoplasmic reticulum (ER). It displays in many cell types a predominantly perinuclear or even nuclear localization. IP3R2 is characterized by a high sensitivity to both IP3 and ATP and is biphasically regulated by Ca2+. Interestingly, ATP stimulates IP3R2 independently of the cytosolic [Ca2+]. Furthermore, IP3R2 is modulated by phosphorylation events mediated by e.g. protein kinase A, Ca2+/calmodulin-dependent kinase II and protein kinase C. In addition to its regulation by protein kinase A, IP3R2 forms a complex with adenylate cyclase 6 and is directly regulated by cAMP, thereby linking in a new way Ca2+-dependent and cAMP-dependent signalling. Finally, in the ER, IP3R2 is less mobile than the other IP3R isoforms, while its functional properties appear dominant in heterotetramers. These properties make the IP3R2 a Ca2+ channel with exquisite properties for setting up intracellular Ca2+ signals with unique characteristics. IP3R2 plays a crucial role in the function of secretory cell types (e.g. pancreatic acinar cells, hepatocytes, salivary gland, eccrine sweat gland). In cardiac myocytes, the role of IP3R2 appears more complex, because, together with IP3R1, it is needed for normal cardiogenesis, while its aberrant activity is implicated in cardiac hypertrophy and arrhythmias. Moreover, IP3R2 expression is driven by IP3-induced Ca2+ release leading to a self-perpetuating system of cardiac hypertrophy. Most importantly, its high sensitivity to IP3 makes IP3R2 a target for anti-apoptotic proteins (e.g. Bcl-2) in B-cell cancers. Disrupting IP3R/Bcl-2 interaction therefore leads in those cells to increased Ca2+ release and apoptosis. Intriguingly, IP3R2 is not only implicated in apoptosis but also in the induction of senescence, another tumour-suppressive mechanism. These results were the first to unravel the physiological and pathophysiological role of IP3R2 and we anticipate that further progress will soon be made in understanding the function of IP3R2 in various tissues and organs.

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“…Moreover, expression levels are directly related to aggressiveness of the tumor [39]. In addition, it has been also reported that depletion of mutated K-Ras in a colon cancer cell line changes Ca 2+ store content and susceptibility to apoptosis by promoting changes in expression of IP 3 R isoforms [40]. Therefore, IP 3 Rs are critical players in Ca 2+ remodeling in colon cancer, contributing likely to changes in Ca 2+ store content and susceptibility to apoptosis.…”

Section: Resultsmentioning

confidence: 99%

Transcriptomic Analysis of Calcium Remodeling in Colorectal Cancer

Pérez-Riesgo

Gutiérrez

Ubierna

et al. 2017

IJMS

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Colorectal cancer (CRC) cells undergo the remodeling of intracellular Ca2+ homeostasis, which contributes to cancer hallmarks such as enhanced proliferation, invasion and survival. Ca2+ remodeling includes critical changes in store-operated Ca2+ entry (SOCE) and Ca2+ store content. Some changes have been investigated at the molecular level. However, since nearly 100 genes are involved in intracellular Ca2+ transport, a comprehensive view of Ca2+ remodeling in CRC is lacking. We have used Next Generation Sequencing (NGS) to investigate differences in expression of 77 selected gene transcripts involved in intracellular Ca2+ transport in CRC. To this end, mRNA from normal human colonic NCM460 cells and human colon cancer HT29 cells was isolated and used as a template for transcriptomic sequencing and expression analysis using Ion Torrent technology. After data transformation and filtering, exploratory analysis revealed that both cell types were well segregated. In addition, differential gene expression using R and bioconductor packages show significant differences in expression of selected voltage-operated Ca2+ channels and store-operated Ca2+ entry players, transient receptor potential (TRP) channels, Ca2+ release channels, Ca2+ pumps, Na+/Ca2+ exchanger isoforms and genes involved in mitochondrial Ca2+ transport. These data provide the first comprehensive transcriptomic analysis of Ca2+ remodeling in CRC.

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Oncogenic K-Ras suppresses IP3-dependent Ca2+ release through remodeling of IP3Rs isoform composition and ER luminal Ca2+ levels in colorectal cancer cell lines

Abstract: BSTRACTThe GTPase Ras is a molecular switch engaged downstream of G-protein-coupled receptors and receptor tyrosine kinases that controls multiple cell-fate-determining signalling pathways.

Cited by 69 publications

References 116 publications

Crosstalk between calcium and reactive oxygen species signaling in cancer

Crosstalk between calcium and reactive oxygen species signaling in cancer

The type 2 inositol 1,4,5-trisphosphate receptor, emerging functions for an intriguing Ca2+-release channel

Transcriptomic Analysis of Calcium Remodeling in Colorectal Cancer

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