The role of metallothionein in oncogenesis and cancer prognosis

Pedersen, Mogens Theisen; Larsen, Agnete; Stoltenberg, Meredin; Penkowa, Milena

doi:10.1016/j.proghi.2008.10.001

Cited by 179 publications

(228 citation statements)

References 160 publications

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“…29,[53][54][55][56][57] These proteins are often overexpressed in various cancers, making them more resistant to irradiation and drugs that induce oxidative stress. 58 In the present work, MT1A and MT2A were found poorly expressed in HTC cells under basal conditions, but were easily upregulated by ZnCl 2 . We also provide evidence that transiently overexpressed MT2A-GFP is sequestered in autophagosomes during starvationinduced autophagy and that some of it eventually relocalizes to lysosomes.…”

Section: Discussionsupporting

confidence: 45%

Autophagy of metallothioneins prevents TNF-induced oxidative stress and toxicity in hepatoma cells

et al. 2015

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, tandem fluorescent microtubule-associated protein 1 light chain 3 A/B (green/red fluorescent proteins chimera); TNFRSF1A/TNFR1, tumor necrosis factor receptor superfamily member 1A; TNFRSF1B/TNFR2, tumor necrosis factor receptor superfamily member 1B.Lysosomal membrane permeabilization (LMP) induced by oxidative stress has recently emerged as a prominent mechanism behind TNF cytotoxicity. This pathway relies on diffusion of hydrogen peroxide into lysosomes containing redox-active iron, accumulated by breakdown of iron-containing proteins and subcellular organelles. Upon oxidative lysosomal damage, LMP allows relocation to the cytoplasm of low mass iron and acidic hydrolases that contribute to DNA and mitochondrial damage, resulting in death by apoptosis or necrosis. Here we investigate the role of lysosomes and free iron in death of HTC cells, a rat hepatoma line, exposed to TNF following metallothionein (MT) upregulation. Iron-binding MT does not normally occur in HTC cells in significant amounts. Intracellular iron chelation attenuates TNF and cycloheximide (CHX)-induced LMP and cell death, demonstrating the critical role of this transition metal in mediating cytokine lethality. MT upregulation, combined with starvation-activated MT autophagy almost completely suppresses TNF and CHX toxicity, while impairment of both autophagy and MT upregulation by silencing of Atg7, and Mt1a and/or Mt2a, respectively, abrogates protection. Interestingly, MT upregulation by itself has little effect, while stimulated autophagy alone depresses cytokine toxicity to some degree. These results provide evidence that intralysosomal iron-catalyzed redox reactions play a key role in TNF and CHX-induced LMP and toxicity. The finding that chelation of intralysosomal iron achieved by autophagic delivery of MT, and to some degree probably of other ironbinding proteins as well, into the lysosomal compartment is highly protective provides a putative mechanism to explain autophagy-related suppression of death by TNF and CHX.

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Section: Discussionsupporting

confidence: 45%

Autophagy of metallothioneins prevents TNF-induced oxidative stress and toxicity in hepatoma cells

et al. 2015

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“…On the other hand, MT2A and total MTs protein levels were higher in chemoresistant cell lines. Many reports have suggested MT expression to be associated with chemoresistance rather than chemosensitivity, although a causal relationship has not been conclusively established (4,5). Our study suggests that different MT isoforms might be differently associated with either chemoresistance or sensitivity, and that this should be studied in further detail to unravel their possible predictive value.…”

Section: Discussionmentioning

confidence: 66%

“…Our study suggests that different MT isoforms might be differently associated with either chemoresistance or sensitivity, and that this should be studied in further detail to unravel their possible predictive value. MT biology is certainly different in different tumor types (4), but at least the MT1G isoform is uniformly reported as having tumor suppressor phenotypes, and therefore its reinduction in tumor cells is a very interesting therapeutic strategy. Another way to reinduce MTs synthesis in tumor cells is by zinc treatment, which is also cytotoxic to tumor cells at high doses.…”

Section: Discussionmentioning

confidence: 99%

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Metallothionein 1G and Zinc Sensitize Human Colorectal Cancer Cells to Chemotherapy

Arriaga

Greco

Mordoh

et al. 2014

Molecular Cancer Therapeutics

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Metallothioneins (MT) are a family of low molecular weight proteins that are silenced during colorectal cancer progression, mainly through epigenetic mechanisms, and this loss is associated with poor survival. In this article, we show that overexpression of the MT1G isoform sensitizes colorectal cell lines to the chemotherapeutic agents oxaliplatin (OXA) and 5-fluorouracil (5-FU), in part through enhancing p53 and repressing NF-kB activity. Despite being silenced, MTs can be reinduced by histone deacetylase inhibitors such as trichostatin A and sodium butyrate. In fact, this induction contributes to the cytotoxicity of these agents, given that silencing of MTs by siRNAs reduces their growth-inhibitory activities. Zinc ions also potently enhance MT expression and are cytotoxic to cancer cells. We show for the first time that OXA and 5-FU induce higher levels of intracellular labile zinc, as measured using the fluorescent probe FLUOZIN-3, and that such zinc contributes to the activation of p53 and repression of NF-kB. Addition of zinc enhanced growth inhibition by OXA and 5-FU, and was also capable of resensitizing 5-FU-resistant cell lines to levels comparable with sensitive cell lines. This effect was MT independent because silencing MTs did not affect zinc cytotoxicity. In conclusion, we show that MT induction and zinc administration are novel strategies to sensitize colorectal cancer cells to presently utilized chemotherapeutic agents. Mol Cancer Ther; 13(5); 1369-81. Ó2014 AACR.

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“…Many functions have been attributed to this redox-active protein, including zinc homeostasis; heavy metal detoxification; metal exchange; metal transfer; and protection against oxidative damage, inflammatory responses, and other cellular stresses (4 -6). Changes in MT expression have been associated with human pathologies including cadmium-induced renal toxicity (7), neurodegeneration (8), and many forms of cancer (9,10). The understanding of these changes is complicated by the 11 functional MT genes, seven pseudogenes, and four MT-like genes encoded in the genome, most of which contain only small differences in amino acid sequence (11).…”

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confidence: 99%

Quantitation of Human Metallothionein Isoforms: A Family of Small, Highly Conserved, Cysteine-rich Proteins

Mehus

Muhonen

Garrett

et al. 2014

Molecular & Cellular Proteomics

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Human metallothioneins (MTs) are important regulators of metal homeostasis and protectors against oxidative damage. Their altered mRNA expression has been correlated with metal toxicity and a variety of cancers. Current immunodetection methods lack the specificity to distinguish all 12 human isoforms. Each, however, can be distinguished by the mass of its acetylated, cysteine-rich, hydrophilic N-terminal tryptic peptides. These properties were exploited to develop a bottom-up MALDI-TOF/TOF-MS-based method for their simultaneous quantitation. Key features included enrichment of N-terminal acetylated peptides by strong cation exchange chromatography, optimization of C18 reversed-phase chromatography, and control of methionine oxidation. Combinations of nine isoforms were identified in seven cell lines and two tissues. Relative quantitation was accomplished by comparing peak intensities of peptides generated from pooled cytosolic proteins alkylated with 14 N-or 15 N-iodoacetamide. Absolute quantitation was achieved using 15 Niodoacetamide-labeled synthetic peptides as internal standards. The method was applied to the cadmium induction of MTs in human kidney HK-2 epithelial cells expressing recombinant MT-3. Seven isoforms were detected with abundances spanning almost 2 orders of magnitude and inductions up to 12-fold. The protein-to-mRNA ratio for MT-1E was one-tenth that of other MTs, suggesting isoform-specific differences in protein expression efficiency. Differential expression of MT-1G1 and MT-1G2 suggested tissue-and cell-specific alternative splicing for the MT-1G isoform. Protein expression of MT isoforms was also evaluated in human breast epithelial cancer cell lines. Estrogen-receptor-positive cell lines expressed only MT-2 and MT-1X, whereas estrogen-receptor-negative cell lines additionally expressed MT-1E. The combined expression of MT isoforms was 38-fold greater in estrogen-receptornegative cell lines than in estrogen-receptor-positive cells. These findings demonstrate that individual human MT isoforms can be accurately quantified in cells and tissues at the protein level, complementing and expanding mRNA measurement as a means for evaluating MTs as potential biomarkers for cancers or heavy metal toxicity. Molecular & Cellular

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The role of metallothionein in oncogenesis and cancer prognosis

Cited by 179 publications

References 160 publications

Autophagy of metallothioneins prevents TNF-induced oxidative stress and toxicity in hepatoma cells

Autophagy of metallothioneins prevents TNF-induced oxidative stress and toxicity in hepatoma cells

Metallothionein 1G and Zinc Sensitize Human Colorectal Cancer Cells to Chemotherapy

Quantitation of Human Metallothionein Isoforms: A Family of Small, Highly Conserved, Cysteine-rich Proteins

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