MCU-dependent negative sorting of miR-4488 to extracellular vesicles enhances angiogenesis and promotes breast cancer metastatic colonization

Zheng, X.F. Steven; Lu, Sitong; He, Zhanxin; Huang, Hongyun; Yao, Zhuocheng; Miao, Yutian; Cheng, Can; Zou, Fei

doi:10.1038/s41388-020-01514-6

Cited by 35 publications

(26 citation statements)

References 46 publications

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“…Several FDA-approved anticancer agents (such as 5-fluorouracil, cisplatin, tamoxifen, paclitaxel, and doxorubicin) and drugs against other disease conditions (such as leflunomide, tolvaptan, and teriflunomide) can impact Ca 2+ signaling machinery [ 484 , 485 ]. Some of these drugs, formulated as prodrugs or nanocarrier loads, are under investigation as antagonists of cancer-promoting Ca 2+ signaling See Figure 12 [ 46 , 226 , 227 , 252 , 440 , 441 , 486 , 487 , 488 , 489 , 490 , 491 , 492 , 493 , 494 , 495 , 496 , 497 , 498 , 499 , 500 , 501 , 502 , 503 , 504 , 505 , 506 , 507 , 508 , 509 , 510 , 511 , 512 , 513 , 514 , 515 , 516 , 517 , 518 , 519 , 520 , 521 , 522 , 523 , …”

Section: Conclusion and Discussionmentioning

confidence: 99%

“…For therapy-resistant medulloblastoma and ovarian cancer, on the other hand, knockdown of NCX1 results in sensitization of these cancers to ionizing radiation and cisplatin [ 250 , 251 ]. Similarly, OSW-1, a natural saponin, and potential anticancer treatment blocks NCX activity in acute leukemia cell line (HL-60) and induces cytotoxicity via accumulation of excess Ca 2+ ion in the cytosol [ 252 ]. In cancer cells exposed to hypoxia, the reverse mode NCX functioning is coupled to carbonic anhydrase IX (CA1X) and sodium-hydrogen exchanger (NHE1) for converting the intracellular proton load (occurring due to metabolic changes during hypoxia) into interstitial acidosis [ 253 , 254 ].…”

Section: Redistribution Of Intracellular Ca 2+ and Hijack Of Its Regulatory Machinery In Cancer Cellsmentioning

confidence: 99%

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Advances in Intracellular Calcium Signaling Reveal Untapped Targets for Cancer Therapy

2021

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Intracellular Ca2+ distribution is a tightly regulated process. Numerous Ca2+ chelating, storage, and transport mechanisms are required to maintain normal cellular physiology. Ca2+-binding proteins, mainly calmodulin and calbindins, sequester free intracellular Ca2+ ions and apportion or transport them to signaling hubs needing the cations. Ca2+ channels, ATP-driven pumps, and exchangers assist the binding proteins in transferring the ions to and from appropriate cellular compartments. Some, such as the endoplasmic reticulum, mitochondria, and lysosomes, act as Ca2+ repositories. Cellular Ca2+ homeostasis is inefficient without the active contribution of these organelles. Moreover, certain key cellular processes also rely on inter-organellar Ca2+ signaling. This review attempts to encapsulate the structure, function, and regulation of major intracellular Ca2+ buffers, sensors, channels, and signaling molecules before highlighting how cancer cells manipulate them to survive and thrive. The spotlight is then shifted to the slow pace of translating such research findings into anticancer therapeutics. We use the PubMed database to highlight current clinical studies that target intracellular Ca2+ signaling. Drug repurposing and improving the delivery of small molecule therapeutics are further discussed as promising strategies for speeding therapeutic development in this area.

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Section: Conclusion and Discussionmentioning

confidence: 99%

Section: Redistribution Of Intracellular Ca 2+ and Hijack Of Its Regulatory Machinery In Cancer Cellsmentioning

confidence: 99%

Advances in Intracellular Calcium Signaling Reveal Untapped Targets for Cancer Therapy

2021

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“…It has been well documented that calcium ion, one of the most important second messenger molecules, harbors vital roles in a broad spectrum of physical processes including cell proliferation, apoptosis, autophagy and metabolism [18]. In recent years, accumulating evidence indicates that deregulation of mitochondrial calcium uniporter complex is associated with various types of cancers including breast cancer [19], hepatocellular carcinoma (HCC) [20], colon cancer [9] and pancreatic cancer [21]. Since mitochondrial calcium uniporter (MCU) complex are mainly responsible to regulate calcium homeostasis in mitochondria, it is thus suggested that altered calcium ion level is linked to tumor growth, progression and metastasis [22].…”

Section: Discussionmentioning

confidence: 99%

MCUR1 Promotes Osteosarcoma Cell Growth Through AKT/p53 Pathway

Wang

Tan

Hou

et al. 2021

Preprint

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Background: Osteosarcoma (OS) is one of the most aggressive malignant bone tumor worldwide. This study focuses on investigating the mechanism underlying the mitochondrial calcium uniporter regulator 1 (MCUR1)-mediated osteosarcoma (OS) cell growth. Methods: A total of 49 patients diagnosed as OS in our hospital were included in the current study. The expression of MCUR1 in human OS tissues and various OS cell lines was detected by immunohistochemical staining (IHC) and western blot analysis, respectively. The effect of MCUR1 on AKT/p53 pathway and its correlation with miR-506-3p were investigated by a series of experiments including MTS, QRT-PCR, Western blot and IHC. Results: Our data showed that MCUR1 was highly overexpressed in OS tumor tissues compared with the para-carcinoma tissues (P<0.01). The Kaplan-Meier analysis showed that high expression level of MCUR1 was linked with poor prognosis of OS patients. Additionally, knockdown of MCUR1 enhanced OS cell apoptosis and decreased the growth of OS cells compared with the corresponding controls (P<0.05). Meanwhile, the expression level of p-AKT was decreased, whereas the protein expression level of p53 was increased in OS cells with MCUR1 downregulation. We also found that the IHC scores of MCUR1 were inversely correlated with that of p53 (r = -0.304, P=0.034). Likewise, the expression of MCUR1 and miR-506-3p in OS tissues were also inversely correlated (r=-0.304, P=0.034). Conclusions: MCUR1 is overexpressed in OS cells and its expression is regulated by miR-506-3p. MCUR1 facilitates the progression of OS through activating AKT/p53 pathway. The data in the current study suggests that MCUR1 may serve as a new target for the diagnosis and treatment of OS.

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“…The mitochondrial Ca 2+ uniporter is located at the mitochondrial membrane of breast cancer cells and regulates tumor proliferation [ 123 , 124 , 125 ], and triple-negative breast cancer cells (MDA-MB-231 and BT-549) express this transporter to a greater degree than non-triple-negative breast cancer cells (T47D, BT-474, and MCF-7) [ 126 ]. Downregulation of the mitochondrial Ca 2+ uniporter through extracellular vesicles suppresses MDA-MB-231 cell colonization [ 126 ]. Additionally, the Ca 2+ -binding protein S100A4 promotes MDA-MB-231 cell colonization [ 127 , 128 ].…”

Section: The Relationship Between Breast Cancer Metastasis and Ca mentioning

confidence: 99%

Ca2+ Signaling as the Untact Mode during Signaling in Metastatic Breast Cancer

Lee

Hong

2021

Cancers

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Metastatic features of breast cancer in the brain are considered a common pathology in female patients with late-stage breast cancer. Ca2+ signaling and the overexpression pattern of Ca2+ channels have been regarded as oncogenic markers of breast cancer. In other words, breast tumor development can be mediated by inhibiting Ca2+ channels. Although the therapeutic potential of inhibiting Ca2+ channels against breast cancer has been demonstrated, the relationship between breast cancer metastasis and Ca2+ channels is not yet understood. Thus, we focused on the metastatic features of breast cancer and summarized the basic mechanisms of Ca2+-related proteins and channels during the stages of metastatic breast cancer by evaluating Ca2+ signaling. In particular, we highlighted the metastasis of breast tumors to the brain. Thus, modulating Ca2+ channels with Ca2+ channel inhibitors and combined applications will advance treatment strategies for breast cancer metastasis to the brain.

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MCU-dependent negative sorting of miR-4488 to extracellular vesicles enhances angiogenesis and promotes breast cancer metastatic colonization

Cited by 35 publications

References 46 publications

Advances in Intracellular Calcium Signaling Reveal Untapped Targets for Cancer Therapy

Advances in Intracellular Calcium Signaling Reveal Untapped Targets for Cancer Therapy

MCUR1 Promotes Osteosarcoma Cell Growth Through AKT/p53 Pathway

Ca2+ Signaling as the Untact Mode during Signaling in Metastatic Breast Cancer

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