Involvement of ORAI1/SOCE in Human AML Cell Lines and Primary Cells According to ABCB1 Activity, LSC Compartment and Potential Resistance to Ara-C Exposure

Lewuillon, Clara; Guillemette, Aurélie; Titah, Sofia; Shaik, Faruk Azam; Jouy, Nathalie; Labiad, Ossama; Farfarellio, Valerio; Laguillaumie, Marie-Océane; Idziorek, Thierry; Barthélémy, Adeline; Peyrouze, Pauline; Berthon, Céline; Tarhan, Mehmet C.; Cheok, Meyling; Quesnel, Bruno; Lemonnier, Loïc; Touil, Yasmine

doi:10.3390/ijms23105555

Cited by 5 publications

(5 citation statements)

References 32 publications

(56 reference statements)

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“…In 6 well plates, the cells were grown for observation. FABP5 expression was evaluated by qRT–PCR and WB technique 96 h after the transfection of cells ( Lewuillon et al, 2022 ).…”

Section: Methodsmentioning

confidence: 99%

Doxorubicin resistance in breast cancer is mediated via the activation of FABP5/PPARγ and CaMKII signaling pathway

Chen

Zhang

et al. 2023

Front. Pharmacol.

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Breast cancer is the most prevalent malignancy among women. Doxorubicin (Dox) resistance was one of the major obstacles to improving the clinical outcome of breast cancer patients. The purpose of this study was to investigate the relationship between the FABP signaling pathway and Dox resistance in breast cancer. The resistance property of MCF-7/ADR cells was evaluated employing CCK-8, Western blot (WB), and confocal microscopy techniques. The glycolipid metabolic properties of MCF-7 and MCF-7/ADR cells were identified using transmission electron microscopy, PAS, and Oil Red O staining. FABP5 and CaMKII expression levels were assessed through GEO and WB approaches. The intracellular calcium level was determined by flow cytometry. Clinical breast cancer patient’s tumor tissues were evaluated by immunohistochemistry to determine FABP5 and p-CaMKII protein expression. In the presence or absence of FABP5 siRNA or the FABP5-specific inhibitor SBFI-26, Dox resistance was investigated utilizing CCK-8, WB, and colony formation methods, and intracellular calcium level was examined. The binding ability of Dox was explored by molecular docking analysis. The results indicated that the MCF-7/ADR cells we employed were Dox-resistant MCF-7 cells. FABP5 expression was considerably elevated in MCF-7/ADR cells compared to parent MCF-7 cells. FABP5 and p-CaMKII expression were increased in resistant patients than in sensitive individuals. Inhibition of the protein expression of FABP5 by siRNA or inhibitor increased Dox sensitivity in MCF-7/ADR cells and lowered intracellular calcium, PPARγ, and autophagy. Molecular docking results showed that FABP5 binds more powerfully to Dox than the known drug resistance-associated protein P-GP. In summary, the PPARγ and CaMKII axis mediated by FABP5 plays a crucial role in breast cancer chemoresistance. FABP5 is a potentially targetable protein and therapeutic biomarker for the treatment of Dox resistance in breast cancer.

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“…In 6 well plates, the cells were grown for observation. FABP5 expression was evaluated by qRT–PCR and WB technique 96 h after the transfection of cells ( Lewuillon et al, 2022 ).…”

Section: Methodsmentioning

confidence: 99%

Doxorubicin resistance in breast cancer is mediated via the activation of FABP5/PPARγ and CaMKII signaling pathway

Chen

Zhang

et al. 2023

Front. Pharmacol.

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“…SOCE is triggered when Orai1 and STIM1/STIM2 proteins interact in response to ER Ca 2+ store depletion. Increased expression of Orai1 or STIM1/STIM2 has been recorded in cell lines derived from AML ( 132 , 133 ), T-ALL ( 134 ), CLL ( 11 ) and various lymphoma cell lines ( 134 , 156 ). Mantle cell lymphoma Rec-1 cell line does not have high expression of Orai1 and STIM1 but Rec-1 and patient cells have significantly higher cytoplasmic Ca 2+ concentrations under physiological conditions compared to normal cells suggesting “leaky SOCE” ( 196 ).…”

Section: Calcium Signaling Deregulation In Blood Cancermentioning

confidence: 99%

“…In the HL-60 APL cell line, silencing of Orai1 and Orai2 reduces cell migration and proliferation ( 132 ). In the KG-1 and U937 AML cell lines, Orai1 contributes to cell proliferation and cell cycle progression ( 133 ). ORAI1 gene expression was increased in peripheral blood mononuclear cells from 9 patients with AML compared with normal cells and correlated with adverse risk in the cohort of 439 AML patients ( 133 ).…”

Section: Calcium Signaling Deregulation In Blood Cancermentioning

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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“…Focusing on SOCE actors, ORAI2 expression is high in HL60 cells, and its knockdown decreases cell proliferation [32]. In parallel, a recent report showed chemoresistance for AML cells treated with cytarabine with elevated ORAI1 expression that confirms the involvement of SOCE in AML cell lines and primary AML blasts, controlling both cell cycle and proliferation in KG1a and U937 cell lines [33].…”

Section: Introductionmentioning

confidence: 97%

STIM2 is involved in the regulation of apoptosis and the cell cycle in normal and malignant monocytic cells

Djordjevic,

Itzykson,

Hague

et al. 2024

Molecular Oncology

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Calcium is a ubiquitous messenger that regulates a wide range of cellular functions, but its involvement in the pathophysiology of acute myeloid leukemia (AML) is not widely investigated. Here, we identified, from an analysis of The Cancer Genome Atlas and genotype‐tissue expression databases, stromal interaction molecule 2 (STIM2) as being highly expressed in AML with monocytic differentiation and negatively correlated with overall survival. This was confirmed on a validation cohort of 407 AML patients. We then investigated the role of STIM2 in cell proliferation, differentiation, and survival in two leukemic cell lines with monocytic potential and in normal hematopoietic stem cells. STIM2 expression increased at the RNA and protein levels upon monocyte differentiation. Phenotypically, STIM2 knockdown drastically inhibited cell proliferation and induced genomic stress with DNA double‐strand breaks, as shown by increased levels of phosphorylate histone H2AXγ (p‐H2AXγ), followed by activation of the cellular tumor antigen p53 pathway, decreased expression of cell cycle regulators such as cyclin‐dependent kinase 1 (CDK1)–cyclin B1 and M‐phase inducer phosphatase 3 (CDC25c), and a decreased apoptosis threshold with a low antiapoptotic/proapoptotic protein ratio. Our study reports STIM2 as a new actor regulating genomic stability and p53 response in terms of cell cycle and apoptosis of human normal and malignant monocytic cells.

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Involvement of ORAI1/SOCE in Human AML Cell Lines and Primary Cells According to ABCB1 Activity, LSC Compartment and Potential Resistance to Ara-C Exposure

Cited by 5 publications

References 32 publications

Doxorubicin resistance in breast cancer is mediated via the activation of FABP5/PPARγ and CaMKII signaling pathway

Doxorubicin resistance in breast cancer is mediated via the activation of FABP5/PPARγ and CaMKII signaling pathway

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

STIM2 is involved in the regulation of apoptosis and the cell cycle in normal and malignant monocytic cells

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