scholarly journals Store-Independent Calcium Entry and Related Signaling Pathways in Breast Cancer

Genes ◽  
2021 ◽  
Vol 12 (7) ◽  
pp. 994
Author(s):  
Mohamed Chamlali ◽  
Lise Rodat-Despoix ◽  
Halima Ouadid-Ahidouch
Keyword(s):  
Breast Cancer ◽  
Signaling Pathways ◽  
Calcium Entry ◽  
Cell Functions ◽  
Fine Tune ◽  
Ca2 Channels ◽  
In Cells

Known as a key effector in breast cancer (BC) progression, calcium (Ca2+) is tightly regulated to maintain the desired concentration to fine-tune cell functions. Ca2+ channels are the main actors among Ca2+ transporters that control the intracellular Ca2+ concentration in cells. It is well known that the basal Ca2+ concentration is regulated by both store-dependent and independent Ca2+ channels in BC development and progression. However, most of the literature has reported the role of store-dependent Ca2+ entry, and only a few studies are focusing on store-independent Ca2+ entry (SICE). In this review, we aim to summarize all findings on SICE in the BC progression field.

scholarly journals Role of the NUDT Enzymes in Breast Cancer

2021 ◽  
Vol 22 (5) ◽  
pp. 2267
Author(s):  
Roni H. G. Wright ◽  
Miguel Beato
Keyword(s):  
Breast Cancer ◽  
Signaling Pathways ◽  
Cancer Progression ◽  
Breast Cancers ◽  
Metastatic Colonization ◽  
Hormone Receptor Positive ◽  
Aggressive Cancer ◽  
Cancer Types ◽  
Metastatic Process

Despite global research efforts, breast cancer remains the leading cause of cancer death in women worldwide. The majority of these deaths are due to metastasis occurring years after the initial treatment of the primary tumor and occurs at a higher frequency in hormone receptor-positive (Estrogen and Progesterone; HR+) breast cancers. We have previously described the role of NUDT5 (Nudix-linked to moiety X-5) in HR+ breast cancer progression, specifically with regards to the growth of breast cancer stem cells (BCSCs). BCSCs are known to be the initiators of epithelial-to-mesenchyme transition (EMT), metastatic colonization, and growth. Therefore, a greater understanding of the proteins and signaling pathways involved in the metastatic process may open the door for therapeutic opportunities. In this review, we discuss the role of NUDT5 and other members of the NUDT family of enzymes in breast and other cancer types. We highlight the use of global omics data based on our recent phosphoproteomic analysis of progestin signaling pathways in breast cancer cells and how this experimental approach provides insight into novel crosstalk mechanisms for stratification and drug discovery projects aiming to treat patients with aggressive cancer.

scholarly journals The role of ferroptosis in breast cancer patients: a comprehensive analysis

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Zeng-Hong Wu ◽  
Yun Tang ◽  
Hong Yu ◽  
Hua-Dong Li
Keyword(s):  
Breast Cancer ◽  
T Cell ◽  
Signaling Pathway ◽  
Differentially Expressed Genes ◽  
Function Analysis ◽  
Cancer Prognosis ◽  
Differentially Expressed ◽  
Immune Checkpoints ◽  
Cell Functions

AbstractBreast cancer (BC) affects the breast tissue and is the second most common cause of mortalities among women. Ferroptosis is an iron-dependent cell death mode that is characterized by intracellular accumulation of reactive oxygen species (ROS). We constructed a prognostic multigene signature based on ferroptosis-associated differentially expressed genes (DEGs). Moreover, we comprehensively analyzed the role of ferroptosis-associated miRNAs, lncRNAs, and immune responses. A total of 259 ferroptosis-related genes were extracted. KEGG function analysis of these genes revealed that they were mainly enriched in the HIF-1 signaling pathway, NOD-like receptor signaling pathway, central carbon metabolism in cancer, and PPAR signaling pathway. Fifteen differentially expressed genes (ALOX15, ALOX15B, ANO6, BRD4, CISD1, DRD5, FLT3, G6PD, IFNG, NGB, NOS2, PROM2, SLC1A4, SLC38A1, and TP63) were selected as independent prognostic factors for BC patients. Moreover, T cell functions, including the CCR score, immune checkpoint, cytolytic activity, HLA, inflammation promotion, para-inflammation, T cell co-stimulation, T cell co-inhibition, and type II INF responses were significantly different between the low-risk and high-risk groups of the TCGA cohort. Immune checkpoints between the two groups revealed that the expressions of PDCD-1 (PD-1), CTLA4, LAG3, TNFSF4/14, TNFRSF4/8/9/14/18/25, and IDO1/2 among others were significantly different. A total of 1185 ferroptosis-related lncRNAs and 219 ferroptosis-related miRNAs were also included in this study. From the online database, we identified novel ferroptosis-related biomarkers for breast cancer prognosis. The findings of this study provide new insights into the development of new reliable and accurate cancer treatment options.

Breast cancer: understanding etiology, addressing molecular signaling pathways, identifying therapeutic targets and strategizing the treatment

2021 ◽  
Vol 12 (3) ◽  
pp. 1757-1769
Author(s):  
Preeti Tanaji Mane ◽  
Sangram Prakash Patil ◽  
Balaji Sopanrao Wakure ◽  
Pravin Shridhar Wakte
Keyword(s):  
Breast Cancer ◽  
Signaling Pathways ◽  
Treatment Options ◽  
Current Treatment ◽  
Vital Role ◽  
Molecular Signaling ◽  
Breast Tumorigenesis ◽  
Non Coding Rnas ◽  
Cycle Regulation

Breast cancer has messed the life of a greater number of women being the most common cancer affecting them worldwide. A number of risk factors contribute the breast malignancy, however, genetic drift is accountable the most. Depending on the cell origin, invasiveness and receptors involved, breast cancer is classified into various subtypes. The accurate diagnosis of breast cancer is important as it defines the prognosis and directs the type of treatment required. A number of major signaling pathways involved in breast tumorigenesis and its development include estrogen receptors (ERs), HER2, Wnt/β-catenin, Notch, Hedgehog (Hh), PI3K and mTOR pathway. Furthermore, certain enzymes like Cyclin dependent kinases and breast tumor kinases also play a vital role in cell cycle regulation and therefore, in the development of breast neoplasms. Recent studies have also enlightened the role of non-coding RNAs in breast cancer development. This review discusses various aspects of breast cancer such as its etiology, subtypes, various signaling pathways involved, targets projected by these pathways and the current treatment options based on a few of these targets. Also, the role of different genes, enzymes and non-coding RNAs related to breast tumorigenesis and development is discussed.

scholarly journals The STIM1 CTID domain determines access of SARAF to SOAR to regulate Orai1 channel function

2013 ◽  
Vol 202 (1) ◽  
pp. 71-79 ◽  
Author(s):  
Archana Jha ◽  
Malini Ahuja ◽  
József Maléth ◽  
Claudia M. Moreno ◽  
Joseph P. Yuan ◽  
...  
Keyword(s):  
Molecular Mechanism ◽  
Cell Damage ◽  
Cell Functions ◽  
Dependent Inactivation ◽  
Dependent Cell ◽  
Inhibitory Domain ◽  
Molecular Components ◽  
Full Activation ◽  
Ca2 Channels

Ca2+ influx by store-operated Ca2+ channels (SOCs) mediates all Ca2+-dependent cell functions, but excess Ca2+ influx is highly toxic. The molecular components of SOC are the pore-forming Orai1 channel and the endoplasmic reticulum Ca2+ sensor STIM1. Slow Ca2+-dependent inactivation (SCDI) of Orai1 guards against cell damage, but its molecular mechanism is unknown. Here, we used homology modeling to identify a conserved STIM1(448–530) C-terminal inhibitory domain (CTID), whose deletion resulted in spontaneous clustering of STIM1 and full activation of Orai1 in the absence of store depletion. CTID regulated SCDI by determining access to and interaction of the STIM1 inhibitor SARAF with STIM1 Orai1 activation region (SOAR), the STIM1 domain that activates Orai1. CTID had two lobes, STIM1(448–490) and STIM1(490–530), with distinct roles in mediating access of SARAF to SOAR. The STIM1(448–490) lobe restricted, whereas the STIM1(490–530) lobe directed, SARAF to SOAR. The two lobes cooperated to determine the features of SCDI. These findings highlight the central role of STIM1 in SCDI and provide a molecular mechanism for SCDI of Orai1.

scholarly journals Pacemaker activity in urethral interstitial cells is not dependent on capacitative calcium entry

2005 ◽  
Vol 289 (3) ◽  
pp. C625-C632 ◽  
Author(s):  
Eamonn Bradley ◽  
Mark A. Hollywood ◽  
Noel G. McHale ◽  
Keith D. Thornbury ◽  
Gerard P. Sergeant
Keyword(s):  
Spontaneous Activity ◽  
Interstitial Cells ◽  
Calcium Entry ◽  
Pacemaker Activity ◽  
Capacitative Calcium Entry ◽  
Intracellular Ca ◽  
Inward Currents ◽  
Rabbit Urethra ◽  
In Cells

The aim of the present study was to investigate the properties and role of capacitative Ca2+ entry (CCE) in interstitial cells (IC) isolated from the rabbit urethra. Ca2+ entry in IC was larger in cells with depleted intracellular Ca2+ stores compared with controls, consistent with influx via a CCE pathway. The nonselective Ca2+ entry blockers Gd3+ (10 μM), La3+ (10 μM), and Ni2+ (100 μM) reduced CCE by 67% ( n = 14), 65% ( n = 11), and 55% ( n = 9), respectively. These agents did not inhibit Ca2+ entry when stores were not depleted. Conversely, CCE in IC was resistant to SKF-96365 (10 μM), wortmannin (10 μM), and nifedipine (1 μM). Spontaneous transient inward currents were recorded from IC voltage-clamped at −60 mV. These events were not significantly affected by Gd3+ (10 μM) or La3+ (10 μM) and were only slightly decreased in amplitude by 100 μM Ni2+. The results from this study demonstrate that freshly dispersed IC from the rabbit urethra possess a CCE pathway. However, influx via this pathway does not appear to contribute to spontaneous activity in these cells.

scholarly journals Support of a bi-faceted role of estrogen receptor β (ERβ) in ERα-positive breast cancer cells

2013 ◽  
Vol 21 (2) ◽  
pp. 143-160 ◽  
Author(s):  
Philip Jonsson ◽  
Anne Katchy ◽  
Cecilia Williams
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Transient Expression ◽  
Therapeutic Potential ◽  
Breast Tumors ◽  
Endocrine Treatment ◽  
Presence And Absence ◽  
Positive Breast Cancer ◽  
In Cells

The expression of estrogen receptor α (ERα) in breast cancer identifies patients most likely to respond to endocrine treatment. The second ER, ERβ, is also expressed in breast tumors, but its function and therapeutic potential need further study. Althoughin vitrostudies have established that ERβ opposes transcriptional and proliferative functions of ERα, several clinical studies report its correlation with proliferative markers and poorer prognosis. The data demonstrate that ERβ opposes ERα are primarily based on transient expression of ERβ. Here, we explored the functions of constitutively expressed ERβ in ERα-positive breast cancer lines MCF7 and T47D. We found that ERβ, under these conditions heterodimerized with ERα in the presence and absence of 17β-estradiol, and induced genome-wide transcriptional changes. Widespread anti-ERα signaling was, however, not observed and ERβ was not antiproliferative. Tamoxifen antagonized proliferation and ER-mediated gene regulation both in the presence and absence of ERβ. In conclusion, ERβ‘s role in cells adapted to its expression appears to differ from its role in cells with transient expression. Our study is important because it provides a deeper understanding of ERβ's role in breast tumors that coexpress both receptors and supports an emerging bi-faceted role of ERβ.

scholarly journals The regulatory role of mitochondrial pora and the possibility of its pharmacological modulation

2014 ◽  
Vol 12 (3) ◽  
pp. 13-19 ◽  
Author(s):  
Yelena Vasilyevna Pozhilova ◽  
Vasiliy Egorovich Novikov ◽  
Olga Sergeevna Levchenkova
Keyword(s):  
Tumor Therapy ◽  
Cell Functions ◽  
Pathological Conditions ◽  
Target Action ◽  
Mechanisms Of Adaptation ◽  
Postischemic Period ◽  
Ischemic Diseases ◽  
Pharmacological Regulation ◽  
In Cells

The review is devoted to the role of mitochondrial Ca2+-dependent pore (mPTP) in the regulation of metabolic processes in cells under physiological and pathological conditions. The mechanisms of reperfusion injury in the postischemic period involving mPTP are discussed in the paper. The possibilities of pharmacological regulation of metabolic and functional processes in cells by target action on mPTP work are assessed. This approach allows to regulate key cell functions, stimulating either mechanisms of adaptation and survival in extreme conditions or apoptosis. Pharmacological modulators of the mitochondrial pore as drugs have promising value for treatment of ischemic diseases as well as tumor therapy.

Regulation of Runx2 and its signaling pathways by microRNAs in breast cancer metastasis

2020 ◽  
Vol 21 ◽  
Author(s):  
Shivashankar Pranavkrishna ◽  
Ganesh Sanjeev ◽  
Ravishkumar L. Akshaya ◽  
Muthukumar Rohini ◽  
Nagarajan Selvamurugan
Keyword(s):  
Breast Cancer ◽  
Transcription Factor ◽  
Signaling Pathways ◽  
Cancer Metastasis ◽  
Breast Cancer Metastasis ◽  
Primary Research ◽  
Research Focus ◽  
Runx2 Expression ◽  
Major Threat

: Posing as a major threat among women globally, breast cancer (BC) emerges as a primary research focus for several researchers. Although various therapeutic regimens are available, there is an increased chance of metastasis of BC cells, which raises the severity of this malignancy. Of multiple preferred secondary targets, metastasis to bone is extensively studied. Besides deemed as a bone transcription factor, Runx2 also acts as a metastatic factor that promotes growth and metastasis of BC cells. Studies have reported the significant role of microRNAs (miRNAs) in BC pathogenesis and metastasis by governing Runx2 expression. Additionally, dysregulation of the signaling pathways, including Wnt/β-catenin, TGF-β, Notch, and PI3K/AKT, have been observed to influence the expression of Runx2 in BC cells. In this review, we have aimed to highlight the regulatory role of miRNAs in targeting Runx2 both directly and indirectly by governing respective signaling pathways during bone metastasis of BC.

The Role of the PI3K-AKT-mTOR Pathway in NK Cell Anti-Tumor Reactivity.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3690-3690
Author(s):  
Matthias Krusch ◽  
Julia Salih ◽  
Ingrid Kumbier ◽  
Carolin Fenner ◽  
Lothar Kanz ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Nk Cells ◽  
Signaling Pathways ◽  
Nk Cell ◽  
Mtor Pathway ◽  
Target Cells ◽  
Cellular Cytotoxicity ◽  
Cell Functions ◽  
Ifn Γ

Abstract Abstract 3690 Poster Board III-626 The phosphatidylinositol 3-kinase – protein kinase B – mammalian target of rapamycin (PI3K – AKT – mTOR) pathway was found to be abnormally activated in many malignancies. Thus, protein kinase (PK) inhibitors (PKI) targeting different signaling molecules of this pathway are presently under clinical evaluation e.g. in sarcoma, multiple myeloma, or renal cell cancer. However, PK are also responsible for most of the signal transduction in immune effector cells and control various effector mechanisms including proliferation, cellular cytotoxicity, and cytokine release. Among those immunoregulatory signaling pathways, the PI3K – AKT – mTOR pathway was found to play a central role in TLR-mediated release of cytokines in macrophages and DC as well as in the regulation of T cell functions. Little is known about the role of this pathway in NK cell-mediated anti-tumor reactivity. Here we analyzed the tumor cell-induced activation of PI3K, AKT, and mTOR in NK cells and the consequences of an inhibition of these molecules by therapeutic PKI for NK cell anti-tumor reactivity. We found that, in response to tumor target cells, PI3K, AKT, and mTOR are consecutively activated in NK cells as revealed by western blot analyses using phospho-specific antibodies. Presence of the specific PI3K-inhbitor BKM-120 concentration-dependently inhibited cytotoxicity and IFN-g production of NK cells, which is in line with available data defining PI3K as a central regulator of NK cell target recognition. The mTOR inhibitors Sirolimus, Temsirolimus, and Everolimus did not alter cytotoxicity but significantly impaired NK cell IFN-γ production. In contrast, Triciribine, a compound which inhibits the phosphorylation and thus activation of AKT, did not influence cytotoxicity and, tantalizingly, even enhanced NK cell IFN-γ production. Thus, after target cell recognition and the activation of proximal PK like PI3K, different and at least partially independent signaling events govern NK cell cytokine production and cellular cytotoxicity. While the activity of PI3K followed by the activation of mitogen-activated PK is known to be crucial for NK cell cytotoxicity, we here identified the AKT – mTOR pathway as a yet unknown central component in the regulation of NK cell IFN-γ production. Moreover, in light of the important role of NK cells in tumor immune surveillance our data indicate that the choise and dosing of the most suitable PKI for a given cancer patient requires careful consideration. In the future it will be critical to define potential differences in immunosuppressive and immunostimulatory side effects of different compounds among the rapidly growing assortment of multi-targeted PKI to enable therapeutic approaches combining targeting of crucial signaling pathways in tumor cells with immunotherapy. Disclosures: No relevant conflicts of interest to declare.

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