Orai1 Ca2+ channel modulators as therapeutic tools for treating cancer: Emerging evidence!

Mignen, Olivier; Vannier, Jean-Pierre; Schneider, Pascale; Renaudineau, Yves; Abdoul-Azize, Souleymane

doi:10.1016/j.bcp.2023.115955

Cited by 4 publications

(5 citation statements)

References 147 publications

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“…Knockdown of ORAI1 resulted in reduced proliferation, migration, and invasion of two gastric cancer cell lines. Knockdown of ORAI3 significantly reduced SOCE and inhibited proliferation by arresting non-small-cell lung cancer cell lines in the G0/G1 phase [117]. Elevated expression of ORAI1 in human oral cancer led to sustained Ca 2+ influx.…”

Section: Orai Expression and Its Role In Various Cancersmentioning

confidence: 95%

“…The activation of ORAI1 typically triggers calcineurin activation and subsequent nuclear factor of activated T cells (NFAT) translocation to the nucleus [119,120], involved in cell proliferation [121][122][123][124], apoptosis resistance [124], angiogenesis, cell invasion, migration [121,123,125], and metastasis [102,117,126] (Figure 3). The downstream signaling pathways encompass basal Ca 2+ signaling [123], ERK (the extracellular signal-regulated kinase) signaling pathway, AKT/mTOR signaling pathway, focal adhesion turnover [127], FAK (focal adhesion kinase) tyrosine phosphorylation, NFAT signaling, and interleukin-6 (IL-6) signaling [122], among others.…”

Section: Orai Expression and Its Role In Various Cancersmentioning

confidence: 99%

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ORAI Ca2+ Channels in Cancers and Therapeutic Interventions

Zhang,

Wang,

2024

Biomolecules

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The ORAI proteins serve as crucial pore-forming subunits of calcium-release-activated calcium (CRAC) channels, pivotal in regulating downstream calcium-related signaling pathways. Dysregulated calcium homeostasis arising from mutations and post-translational modifications in ORAI can lead to immune disorders, myopathy, cardiovascular diseases, and even cancers. Small molecules targeting ORAI present an approach for calcium signaling modulation. Moreover, emerging techniques like optogenetics and optochemistry aim to offer more precise regulation of ORAI. This review focuses on the role of ORAI in cancers, providing a concise overview of their significance in the initiation and progression of cancers. Additionally, it highlights state-of-the-art techniques for ORAI channel modulation, including advanced optical tools, potent pharmacological inhibitors, and antibodies. These novel strategies offer promising avenues for the functional regulation of ORAI in research and may inspire innovative approaches to cancer therapy targeting ORAI.

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Section: Orai Expression and Its Role In Various Cancersmentioning

confidence: 95%

Section: Orai Expression and Its Role In Various Cancersmentioning

confidence: 99%

ORAI Ca2+ Channels in Cancers and Therapeutic Interventions

Zhang,

Wang,

2024

Biomolecules

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“…In addition to the CRAC channels’ role in many immune cell functions, they are also potential drug targets for the treatment of various inflammatory reactions, allergic diseases [ 118 , 119 ], and many cancer types [ 20 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 ]. Several studies have confirmed that the genetic deletion or inhibition of CRAC channels hinders T cell and mast cell functions and diminishes inflammation of autoimmunity, transplant rejection, and asthma [ 119 ].…”

Section: Introduction—the Role Of Ca 2+ Release-ac...mentioning

confidence: 99%

“…The potential role of CRAC channels in cancer development and progression has been deeply discussed in several recent review articles [ 120 , 122 , 123 , 126 , 128 , 139 , 140 , 141 , 142 , 143 , 144 ]. However, the importance of CRAC channels has been also revealed in Ca 2+ -dependent tumor killing by a subset of lymphocytes such as CTL and NK cells.…”

Section: Introduction—the Role Of Ca 2+ Release-ac...mentioning

confidence: 99%

Synthetic Biology Meets Ca2+ Release-Activated Ca2+ Channel-Dependent Immunomodulation

Bacsa,

Hopl,

Derler

2024

Cells

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Many essential biological processes are triggered by the proximity of molecules. Meanwhile, diverse approaches in synthetic biology, such as new biological parts or engineered cells, have opened up avenues to precisely control the proximity of molecules and eventually downstream signaling processes. This also applies to a main Ca2+ entry pathway into the cell, the so-called Ca2+ release-activated Ca2+ (CRAC) channel. CRAC channels are among other channels are essential in the immune response and are activated by receptor–ligand binding at the cell membrane. The latter initiates a signaling cascade within the cell, which finally triggers the coupling of the two key molecular components of the CRAC channel, namely the stromal interaction molecule, STIM, in the ER membrane and the plasma membrane Ca2+ ion channel, Orai. Ca2+ entry, established via STIM/Orai coupling, is essential for various immune cell functions, including cytokine release, proliferation, and cytotoxicity. In this review, we summarize the tools of synthetic biology that have been used so far to achieve precise control over the CRAC channel pathway and thus over downstream signaling events related to the immune response.

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“…Unlike T cells, the role of Orai1 in B cells is much less known and results from Orai1 -/- knockout mice model supported that SOCE and in turn cell proliferation are significantly attenuated in response to BCR stimulation [13,14], suggesting that Orai1 contributes at least in part to Ca 2+ signaling and effector functions in B cells. By contrast, the role of Orai1 in B cell leukemia remains unknown [15].…”

Section: Introductionmentioning

confidence: 99%

Blocking Orai1 constitutive activity inhibits B-cell cancer migration and synergistically acts with drugs to reduce B-CLL cell survival

Scaviner,

Bagacean,

Christian

et al. 2023

Preprint

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Orai1 channel capacity to control store-operated Ca2+entry (SOCE) and B-cell functions is poorly understood and more specifically in B-cell cancers, including human lymphoma and leukemia. As compared to normal B-cells, Orai1 is overexpressed in B-chronic lymphocytic leukemia (B-CLL) and contributes in resting B-CLL to mediate an elevated basal Ca2+level through a constitutive Ca2+entry, and in BCR-activated B-cell to regulate the Ca2+signaling response. Such observations were confirmed in human B-cell lymphoma and leukemia lines, including RAMOS, JOK-1, MEC-1 and JVM-3 cells. Next, the use of pharmacological Orai1 inhibitors (GSK-7975A and Synta66) blocks constitutive Ca2+entry and in turn affects B-cell cancer (primary and cell lines) survival and migration, controls cell cycle, and induces apoptosis through a mitochondrial and caspase-3 independent pathway. Finally, the added value of Orai1 inhibitors in combination with B-CLL drugs (ibrutinib, idelalisib, rituximab, and venetoclax) on B-CLL survival was tested, showing an additive/synergistic effect including in the B-cell cancer lines. To conclude, this study highlights the pathophysiological role of the Ca2+channel Orai1 in B-cell cancers, and pave the way for the use of ORAI1 modulators as a plausible therapeutic strategy.

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Orai1 Ca2+ channel modulators as therapeutic tools for treating cancer: Emerging evidence!

Cited by 4 publications

References 147 publications

ORAI Ca2+ Channels in Cancers and Therapeutic Interventions

ORAI Ca2+ Channels in Cancers and Therapeutic Interventions

Synthetic Biology Meets Ca2+ Release-Activated Ca2+ Channel-Dependent Immunomodulation

Blocking Orai1 constitutive activity inhibits B-cell cancer migration and synergistically acts with drugs to reduce B-CLL cell survival

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