Metallothionein expression in colorectal cancer: relevance of different isoforms for tumor progression and patient survival

Arriaga, Juan Martín; Levy, Estrella Mariel; Bravo, Alicia; Bayo, S. Morales; Amat, Mora; Aris, Mariana; Hannois, Adrián; Bruno, L; Roberti, María Paula; Loria, Fernando Sánchez; Pairola, Alejandro; Huertas, Eduardo; Mordoh, José; Bianchini, Michele

doi:10.1016/j.humpath.2011.04.015

Cited by 52 publications

(69 citation statements)

References 38 publications

(41 reference statements)

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“…The human colorectal cancer cell lines HCT116 and HT-29 were obtained from the American Tissue Culture Collection (ATCC) and maintained as previously described (13). After all experiments were finalized, both cell lines and their derivatives were subjected to short tandem repeat profiling and compared with the ATCC's database for authentication.…”

Section: Reagents and Cell Linesmentioning

confidence: 99%

“…Quantitative reverse-transcription PCR (qRT-PCR) was used to quantify mRNA levels as previously described (13). The primers used are listed in Supplementary Table S1.…”

Section: Quantitative Reverse Transcription Pcr Western Blotting Anmentioning

confidence: 99%

“…For experiments measuring induction of genes after OXA treatment, 50 mmol/L OXA was used for the times indicated. Detection of MTs by Western blotting and immunofluorescence was done using the anti-MT clone E9 antibody (Dako Corporation) that recognizes all MT1 and 2 isoforms, as described in (13). For Western blotting, anti-p53 clone DO-7 (Sigma) and anti-b actin clone C-74 (Sigma) were used.…”

Section: Quantitative Reverse Transcription Pcr Western Blotting Anmentioning

confidence: 99%

“…We have previously reported that histone deacetylase inhibitors (HDACi) such as TSA and BUT can stimulate MT expression in colon cancer cells (13). These agents are also cytotoxic and are being evaluated in clinical trials as possible new therapeutic drugs (23).…”

Section: Hdac Inhibitors Mediate Cell Death In Part By Stimulating Mtmentioning

confidence: 99%

“…We and others have previously demonstrated that these proteins are progressively silenced during colorectal cancer progression, and that this is associated to poorer patient survival. (12)(13)(14).…”

Section: Introductionmentioning

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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Section: Reagents and Cell Linesmentioning

confidence: 99%

“…Quantitative reverse-transcription PCR (qRT-PCR) was used to quantify mRNA levels as previously described (13). The primers used are listed in Supplementary Table S1.…”

Section: Quantitative Reverse Transcription Pcr Western Blotting Anmentioning

confidence: 99%

Section: Quantitative Reverse Transcription Pcr Western Blotting Anmentioning

confidence: 99%

Section: Hdac Inhibitors Mediate Cell Death In Part By Stimulating Mtmentioning

confidence: 99%

Section: Introductionmentioning

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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Metallothionein 1 family profiling identifies MT1X as a tumor suppressor involved in the progression and metastastatic capacity of hepatocellular carcinoma

Liu

Ye²,

Wu³

et al. 2018

Molecular Carcinogenesis

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Metallothionein 1 (MT1s) is a family of cysteine-rich proteins with diverse functions such as metal homeostasis, oxidative stress, and carcinogenesis. However, its involvement in hepatocellular carcinoma (HCC) remains not fully understood. We aimed to explore the contribution of the individual member of MT1s to HCC. Its member mRNA levels were determined in cohort 1 of normal (n = 30), cirrhotic (n = 30), peritumoral (n = 135), and HCC (n = 135). In cohort 1, seven of eight members were down-regulated during the transition from normal liver to HCC, and only MT1G and MT1X were correlated with tumor features and outcomes. The MT1X was selected to be further stained in cohort 2 consisting of a series of liver nodules (15 normal livers, 33 cirrhotic livers, 12 dysplastic nodules, 31 HCC, and 9 HCC metastasis), and in cohort 3 (HCC, n = 85). In cohort 2, MT1X immunoreactivity was reduced in HCC and lost in metastatic HCC and showed good diagnostic performance for HCC (AUC = 0.754, 95%IC = 0.659-0.849). In cohort 3, MT1X expression in peritumoral tissues was independent predictor for HCC (recurrence free survival: HR = 0.34, 95%CI = 0.17-0.66; overall survival: HR = 0.32, 95%CI = 0.16-0.60). Moreover, we found that ectopic overexpression of MT1X delayed G1/S progression of cell cycle and promoted apoptosis in HCC cells in vitro, and suppressed tumor growth and lung metastasis in nude mice in vivo. We further demonstrated that MT1X induces cell cycle arrest and apoptosis by inactivating NF-κB signaling in HCC. In conclusion, MT1X may serve as a candidate of prognostic indicator and inhibits the progression and metastasis of HCC.

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The Role of Metallothioneins in Carcinogenesis

Dzięgiel

Puła

Kobierzycki

et al. 2016

Metallothioneins in Normal and Cancer Cells

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Metallothionein expression in colorectal cancer: relevance of different isoforms for tumor progression and patient survival

Cited by 52 publications

References 38 publications

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

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

Metallothionein 1 family profiling identifies MT1X as a tumor suppressor involved in the progression and metastastatic capacity of hepatocellular carcinoma

The Role of Metallothioneins in Carcinogenesis

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