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Review
. 2019 Mar 30;11(4):457.
doi: 10.3390/cancers11040457.

STIM-Orai Channels and Reactive Oxygen Species in the Tumor Microenvironment

Janina Frisch  1   2 , Adrian Angenendt  3 , Markus Hoth  4 , Leticia Prates Roma  5   6 , Annette Lis  7
Affiliations
Review

STIM-Orai Channels and Reactive Oxygen Species in the Tumor Microenvironment

Janina Frisch et al. Cancers (Basel). .

Abstract

The tumor microenvironment (TME) is shaped by cancer and noncancerous cells, the extracellular matrix, soluble factors, and blood vessels. Interactions between the cells, matrix, soluble factors, and blood vessels generate this complex heterogeneous microenvironment. The TME may be metabolically beneficial or unbeneficial for tumor growth, it may favor or not favor a productive immune response against tumor cells, or it may even favor conditions suited to hijacking the immune system for benefitting tumor growth. Soluble factors relevant for TME include oxygen, reactive oxygen species (ROS), ATP, Ca2+, H⁺, growth factors, or cytokines. Ca2+ plays a prominent role in the TME because its concentration is directly linked to cancer cell proliferation, apoptosis, or migration but also to immune cell function. Stromal-interaction molecules (STIM)-activated Orai channels are major Ca2+ entry channels in cancer cells and immune cells, they are upregulated in many tumors, and they are strongly regulated by ROS. Thus, STIM and Orai are interesting candidates to regulate cancer cell fate in the TME. In this review, we summarize the current knowledge about the function of ROS and STIM/Orai in cancer cells; discuss their interdependencies; and propose new hypotheses how TME, ROS, and Orai channels influence each other.

Keywords: H2O2; Orai; STIM; calcium; reactive oxygen species; tumor microenvironment.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
An overview of the tumor microenvironment (TME): The TME is composed by a diverse range of cell types, including tumor cells, immune cells, epithelial cells, and stromal cells. Areas of low nutrients and O2 result in necrotic regions. The TME controls tumor growth by diverse mechanisms that are further discussed in the text.
Figure 2
Figure 2
Store-operated Ca2+ entry (SOCE) by stromal-interaction molecule (STIM)/Orai channels in cancer cells: Following the stimulation of G protein- or tyrosine kinase-coupled (G/T) receptors (R), phospholipase C (PLC) hydrolyses phosphatidylinositol 4,5-bisphosphate (PIP2) to inositol trisphosphate (IP3). The latter binds to its receptor, a Ca2+ release channel in the endoplasmic reticulum (ER) membrane and opens it, which induces the Ca2+ depletion of ER Ca2+ stores. A drop of (Ca2+)ER activates luminal Ca2+ sensor proteins, the STIMs. Activated STIMs oligomerize and move to the plasma membrane where they bind and open Orai channels, leading to a Ca2+ influx across the plasma membrane. Plasma membrane Ca2+ ATPases (PMCAs), Na+–Ca2+ exchangers (NCX), and sarco-/endoplasmic reticulum Ca2+ ATPases (SERCAs) export Ca2+ from the cytosol.
Figure 3
Figure 3
The main sources of ROS production and elimination: ROS can be generated either by activated NADPH oxidases (here represented by NOX2) located in the plasma membrane or by several complexes of the electron transport chain in the inner membrane of mitochondria. Other metabolic enzymes include xanthine oxidase (XO) and cytochrome P450 (CYP450) that directly form superoxide in the cytoplasm. Superoxide dismutases (SODs) can convert •O2¯ to H2O2. SOD1 is located in the cytoplasm, SOD2 is located in the mitochondrial matrix, and SOD3 is located in the extracellular space. The further elimination of H2O2 via catalase, GPX/GSH, and/or PRX/TRX can either be initiated directly in the mitochondrial matrix or in the cytoplasm upon the transport of H2O2 via aquaporins. CYP450: cytochrome P450; IMM: inner mitochondrial membrane; OMM: outer mitochrondrial membrane; PM: plasma membrane; VDAC: voltage-dependent anion channel; XO: xanthine oxidase.
Figure 4
Figure 4
ROS in the TME: Non cancer-related ROS can be deleterious for healthy tissue and thereby lead to tumor initiation and promotion via DNA damage and the impairment of signaling pathways, transcription factor expression, and epigenetic changes. After the tumor initiation upregulation of oncogenes, the loss of tumor suppressor genes, mitochondria mutations, and hypoxic conditions can lead to further elevated tumor-related ROS levels. In a positive feedback loop system, rising ROS levels in the TME can in turn support tumor progression, angiogenesis, invasion, and metastasis via an amplification of the pathways involved in initiation and promotion. Finally, to protect against threshold-crossing toxic ROS levels, tumor cells initiate the upregulation of antioxidant defense mechanisms in order to prevent from ROS-related deleterious events like apoptosis or necroptosis.
Figure 5
Figure 5
ROS interferes with STIM and Orai: Orai1 and Orai2 are blocked by ROS due to an oxidation of C195. Since Orai3 has no cysteine but a glycine on amino acid position 195 (G195), Orai3 channels are ROS-insensitive. ROS have an activating effect on STIM1. An S-glutathionylation (SG) of C56 renders STIM1 constitutively active. This has been reported to activate Orai channels without prior store-depletion (see text for details). R: receptor; G/T: G protein/tyrosine kinase; PLC: phospholipase C; PIP2: phosphatidylinositol 4,5-bisphosphate; IP3: inositol trisphosphate; ER: endoplasmic reticulum.
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