The unique C- and N-terminal sequences of Metallothionein isoform 3 mediate growth inhibition and Vectorial active transport in MCF-7 cells

Voels, Brent; Wang, Liping; Sens, Donald A.; Garrett, Scott H.; Zhang, Ke; Somji, Seema

doi:10.1186/s12885-017-3355-9

Cited by 4 publications

(4 citation statements)

References 55 publications

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“…For example, MT3 gene knock out showed an effect on post-radiation induced survival of glioma cells [ 87 ]. In MCF-7 cells, a breast cancer cell line, the C- and N-terminal of MT3 contributed to the growth inhibition of cancer cells [ 88 ]. Furthermore, MTs expression level or polymorphisms are used to diagnose risks of various cancers such as gastric cancer, colorectal cancer, breast cancer, and hematological malignancies, or to predict cancer progression [ 89 ].…”

Section: Introductionmentioning

confidence: 99%

Metallothionein-3 as a multifunctional player in the control of cellular processes and diseases

Koh

Lee

2020

Mol Brain

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Transition metals, such as iron, copper, and zinc, play a very important role in life as the regulators of various physiochemical reactions in cells. Abnormal distribution and concentration of these metals in the body are closely associated with various diseases including ischemic seizure, Alzheimer’s disease, diabetes, and cancer. Iron and copper are known to be mainly involved in in vivo redox reaction. Zinc controls a variety of intracellular metabolism via binding to lots of proteins in cells and altering their structure and function. Metallothionein-3 (MT3) is a representative zinc binding protein predominant in the brain. Although the role of MT3 in other organs still needs to be elucidated, many reports have suggested critical roles for the protein in the control of a variety of cellular homeostasis. Here, we review various biological functions of MT3, focusing on different cellular molecules and diseases involving MT3 in the body.

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Section: Introductionmentioning

confidence: 99%

Metallothionein-3 as a multifunctional player in the control of cellular processes and diseases

Koh

Lee

2020

Mol Brain

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“…The finding that the unique C-terminal sequence of MT-3 can promote vectorial active transport when inserted into the MT-1E gene is not a unique finding for renal HK-2 cells. The stable transfection of MT-1E containing the unique C-terminal sequence of MT-3 into MCF-7, a breast cancer cell line, has also been shown to induce dome formation in the stable transformants [ 68 ]. Together these findings suggest that the unique C-terminal insert of MT-3 allows an interaction to be formed with β-actin, myosin-9, and tropomyosin 3 and that this promotes vectorial active transport and an increase in the differentiated function of the epithelial cells.…”

Section: Discussionmentioning

confidence: 99%

Protein interactions with metallothionein-3 promote vectorial active transport in human proximal tubular cells

et al. 2022

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Metallothionein 3 (MT-3) is a small, cysteine-rich protein that binds to essential metals required for homeostasis, as well as to heavy metals that have the potential to exert toxic effects on cells. MT-3 is expressed by epithelial cells of the human kidney, including the cells of the proximal tubule. Our laboratory has previously shown that mortal cultures of human proximal tubular (HPT) cells express MT-3 and form domes in the cell monolayer, a morphological feature indicative of vectorial active transport, an essential function of the proximal tubule. However, an immortalized proximal tubular cell line HK-2 lacks the expression of MT-3 and fails to form domes in the monolayer. Transfection of HK-2 cells with the MT-3 gene restores dome formation in these cells suggesting that MT-3 is required for vectorial active transport. In order to determine how MT-3 imparts this essential feature to the proximal tubule, we sought to identify proteins that interact either directly or indirectly with MT-3. Using a combination of pulldowns, co-immunoprecipitations, and mass spectrometry analysis, putative protein interactants were identified and subsequently confirmed by Western analysis and confocal microscopy, following which proteins with direct physical interactions were investigated through molecular docking. Our data shows that MT-3 interacts with myosin-9, aldolase A, enolase 1, β-actin, and tropomyosin 3 and that these interactions are maximized at the periphery of the apical membrane of doming proximal tubule cells. Together these observations reveal that MT-3 interacts with proteins involved in cytoskeletal organization and energy metabolism, and these interactions at the apical membrane support vectorial active transport and cell differentiation in proximal tubule cultures.

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“…This makes MT3 a unique member of MTs family. Recently, expression of MT3-encoding mRNA MT3 has been associated with a worse prognosis of breast cancer and neuroblastoma patients, and it has also been shown that MT3 expression tightly correlates with the poor outcomes of chemotherapy [25][26][27]. However, the role of MT3 in HCC remains unknown.…”

Section: Introductionmentioning

confidence: 99%

Metallothionein-3 is a multifunctional driver that modulates the development of sorafenib-resistant phenotype in hepatocellular carcinoma cells

Rodrigo,

Michalkova,

Jimenez

et al. 2024

Biomark Res

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Background & aims Metallothionein-3 (hMT3) is a structurally unique member of the metallothioneins family of low-mass cysteine-rich proteins. hMT3 has poorly characterized functions, and its importance for hepatocellular carcinoma (HCC) cells has not yet been elucidated. Therefore, we investigated the molecular mechanisms driven by hMT3 with a special emphasis on susceptibility to sorafenib. Methods Intrinsically sorafenib-resistant (BCLC-3) and sensitive (Huh7) cells with or without up-regulated hMT3 were examined using cDNA microarray and methods aimed at mitochondrial flux, oxidative status, cell death, and cell cycle. In addition, in ovo/ex ovo chick chorioallantoic membrane (CAM) assays were conducted to determine a role of hMT3 in resistance to sorafenib and associated cancer hallmarks, such as angiogenesis and metastastic spread. Molecular aspects of hMT3-mediated induction of sorafenib-resistant phenotype were delineated using mass-spectrometry-based proteomics. Results The phenotype of sensitive HCC cells can be remodeled into sorafenib-resistant one via up-regulation of hMT3. hMT3 has a profound effect on mitochondrial respiration, glycolysis, and redox homeostasis. Proteomic analyses revealed a number of hMT3-affected biological pathways, including exocytosis, glycolysis, apoptosis, angiogenesis, and cellular stress, which drive resistance to sorafenib. Conclusions hMT3 acts as a multifunctional driver capable of inducing sorafenib-resistant phenotype of HCC cells. Our data suggest that hMT3 and related pathways could serve as possible druggable targets to improve therapeutic outcomes in patients with sorafenib-resistant HCC.

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The unique C- and N-terminal sequences of Metallothionein isoform 3 mediate growth inhibition and Vectorial active transport in MCF-7 cells

Cited by 4 publications

References 55 publications

Metallothionein-3 as a multifunctional player in the control of cellular processes and diseases

Metallothionein-3 as a multifunctional player in the control of cellular processes and diseases

Protein interactions with metallothionein-3 promote vectorial active transport in human proximal tubular cells

Metallothionein-3 is a multifunctional driver that modulates the development of sorafenib-resistant phenotype in hepatocellular carcinoma cells

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