Calcium sensing receptor stimulates breast cancer cell migration via the Gβγ-AKT-mTORC2 signaling pathway

Orduña-Castillo, Lennis Beatríz; del-Río-Robles, Jorge Eduardo; García‐Jiménez, Irving; Zavala-Barrera, Cesar; Beltrán‐Navarro, Yarely Mabell; Hidalgo-Moyle, Joseline Janai; Ramírez-Rangel, Iliana; Hernandez-Bedolla, Marco Antonio; Reyes-Ibarra, Alma P.; Valadez-Sánchez, Margarita; Vázquez‐Prado, José; Reyes‐Cruz, Guadalupe

doi:10.1007/s12079-021-00662-y

Cited by 9 publications

(3 citation statements)

References 73 publications

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“…G protein-coupled receptor 4 (GPR4) is one of the four receptors of the OGR1 subfamily, which is widely distributed in various human tumor tissue cells and participates in and influences tumorigenesis and development. It was found that malignant tumors can affect the expression of GPR4 and vascular endothelial growth factor (VEGF) and its receptors directly or indirectly due to excessive proliferation, severe local tissue hypoxia, and the formation of an acidic environment [ 16 – 18 ], which affects the microvascular density of tumor tissues and thus the development, infiltration, and metastasis of tumors, and GPR4 plays an essential role in the vascular endothelial cells of angiogenesis. Furthermore, they are involved in related diseases and cancer-related angiogenesis.…”

Section: Introductionmentioning

confidence: 99%

Exploring oncogenes for renal clear cell carcinoma based on G protein-coupled receptor-associated genes

Zhu,

Sun,

Wang

et al. 2023

Discov Onc

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G protein-coupled receptors (GPCRs) are a class of receptors on cell membranes that regulate various biological processes in cells, such as cell proliferation, differentiation, migration, apoptosis, and metabolism, by interacting with G proteins. However, the role of G protein-coupled receptors in predicting the prognosis of renal clear cell carcinoma is still unknown. The transcriptome data and clinical profiles of renal clear cell carcinoma patients, were downloaded from TCGA databases, and the validation group data were downloaded from number GSE167573, including 63 tumor samples and 14 normal samples. Single-cell RNA sequencing data were downloaded from the GEO database, No. GSE152938 and selected samples were used for GSEA enrichment analysis, WGCNA subgroup analysis, single-cell data analysis, and mutation analysis to explore the role of G protein-coupled receptor-related genes in the diagnosis and prognosis of renal clear cell carcinoma and to verify their reliability with cellular experiments. Finally, this study establishes a disease model based on G protein-coupled receptor-related genes, which may help to propose targeted therapeutic regimens in different strata of renal cell carcinoma patients.Author names: Please confirm if the author names are presented accurately and in the correct sequence (given name, middle name/initial, family name). Author: Given name [Lisa Jia] Last name [Tran].It's ok!

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Section: Introductionmentioning

confidence: 99%

Exploring oncogenes for renal clear cell carcinoma based on G protein-coupled receptor-associated genes

Zhu,

Sun,

Wang

et al. 2023

Discov Onc

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“…Studies have shown that VEGFR2 and Gβγ influence tumor development. Gβγ regulates breast cancer cell migration through the AKT signaling 22 and is a critical factor affecting lung cancer metastasis. 23 Abnormal VEGFR2 activation in breast, lung, and colorectal cancers promotes tumor occurrence and development.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of FNDC1 suppresses gastric cancer progression by interfering with Gβγ-VEGFR2 complex formation

Lu¹,

Huang²,

Zeng³

et al. 2023

iScience

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“…Looking beyond AML, CaSR has been linked to the etiology of a variety of cancers (section 2.10.4). Studies on human cell lines have shown that inhibition of CaSR with NPS-2143 is a promising therapy in melanoma (Wang et al, 2018), gastric (Zhang et al, 2020), prostate (Yamamura et al, 2019) and breast cancer (Alqudah et al, 2021;Orduña-Castillo et al, 2021). In addition to cancer, NPS-2143 has been found to be effective in allergic asthma (Yarova et al, 2015b) and chronic obstructive pulmonary disease (Lee et al, 2017) by reducing the airway hyperresponsiveness and inflammation.…”

Section: The Casr Antagonist Nps-2143 Is Effective In Targeting Amlmentioning

confidence: 99%

The role of calcium ions in the leukemic bone marrow microenvironment

Pereira¹

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Leukemia is a cancer of the blood and bone marrow characterized by an uncontrolled proliferation and accumulation of abnormal white blood cells. Leukemia can be classified based on the course of the disease (acute or chronic) and the blood cell type involved (myeloid or lymphocytic), leading to four main subtypes: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL) and chronic myeloid leukemia (CML). Leukemia represents 2.5% of all new cancer cases per year, and survival rates in some leukemias remain low at 40%. The bone marrow microenvironment (BMM) is a system within the bone marrow comprising cellular and acellular components, all of which play a major role in hematopoiesis, providing the physical space where hematopoietic stem cells (HSCs) reside. The BMM interacts with HSCs, offering a “niche” for those cells and in case of leukemia, the BMM has a supportive role in disease maintenance and progression by supporting Leukemia stem cells (LSCs). One of the components of the BMM are calcium ions. Calcium is the most abundant mineral in the body, a key component of bones and is released by parathyroid hormone (PTH) induced bone remodeling. Calcium ions play a role in the localization, engraftment and adhesion of normal HSC to extracellular matrix (ECM) proteins in the BMM via the calcium sensing receptor (CaSR), thereby maintaining normal hematopoiesis. In addition of a major regulator of calcium homeostasis, CaSR contribute to the development of different cancers, functioning as either tumor suppressor or oncogene, depending on the involved tissue. However, the role of CaSR and its associated pathways in the local BMM for the development of leukemia is poorly understood. We hypothesized that calcium ions released from bone, subject to a fine balance between osteoblasts and osteoclasts, and/or CaSR, contribute to development, progression and response to therapy. We have shown that the local calcium concentration forms a gradient in the bone marrow niche and in mice with CML is similarly low as in control mice, but significantly higher in mice suffering from BCR ABL1 driven B ALL or MLL AF9 driven AML. Similarly, the calcium concentration in the human BMM was found to be higher in AML than in other leukemias. Regarding the function of calcium in leukemia cells, we found that AML and CML cells respond differently to calcium exposure, with AML cells exhibiting regulation of cellular processes such as adhesion to the ECM protein fibronectin and migration toward CXCL 12, whereas CML cells remained mostly unaltered. Using genetic deletion or overexpression of CaSR in murine models of leukemia, we observed that CaSR acts as tumor suppressor in BCR-ABL1 driven CML and B ALL and as oncogene in AML. Focusing on AML, our data shows that deficiency of CaSR on LICs leads, on one hand to increased apoptosis, and on the other hand to reduced cell cycle, reactive oxygen species (ROS) production and DNA damage in vivo, which may explain the observed prolongation of survival of mice. Complementary, in vitro experiments demonstrated that cells overexpressing CaSR have a distinct, cancer promoting phenotype compared to wildtype cells. Overexpression of CaSR led to an increase in proliferation, cell cycle, ROS production, DNA damage and reduced apoptosis. We have identified CaSR mediated pathways in AML and shown that CaSR enhances leukemia progression by activating MAPK/ERK and Wnt β catenin signaling. In addition, the CaSR interacting protein filamin A (FLNA) was shown to contribute to aggressive disease in vitro and in vivo. Furthermore, the mechanism underlying the role of CaSR in AML pathogenesis and possible regulation of LSCs was studied. Our findings demonstrated that CaSR ablation reduces myeloid progenitor function and proved that CaSR is required for maintenance of LSC pool by regulating its frequency and function. Further supporting the role of CaSR in LSC maintenance, genes associated with AML stemness and self renewal capacity were upregulated when CaSR was overexpressed and downregulated when CaSR was depleted. Given the role of CaSR in AML, the CaSR antagonist NPS 2143 was tested in vivo. The combination treatment of NPS 2143 with the standard of care, ara C, significantly reduced the tumor burden and prolonged the survival of mice with AML in syngeneic and xenotransplantation experiments. Based on the finding that CaSR functions as a tumor suppressor in CML, treatment of mice with the CaSR agonist cinacalcet in combination with imatinib prolonged survival of mice with CML compared to treatment with the mice given vehicle. Our results suggest that calcium ions stemming from the calcium-rich BMM via CaSR strongly and differentially influence leukemia progression. As an adjunct to existing treatment therapies, targeting of CaSR with specific pharmacologic antagonists may prolong survival of patients with AML.

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Calcium sensing receptor stimulates breast cancer cell migration via the Gβγ-AKT-mTORC2 signaling pathway

Cited by 9 publications

References 73 publications

Exploring oncogenes for renal clear cell carcinoma based on G protein-coupled receptor-associated genes

Exploring oncogenes for renal clear cell carcinoma based on G protein-coupled receptor-associated genes

Inhibition of FNDC1 suppresses gastric cancer progression by interfering with Gβγ-VEGFR2 complex formation

The role of calcium ions in the leukemic bone marrow microenvironment

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