Diversity of metallothionein content and subcellular localization in the National Cancer Institute tumor panel

Woo, Elizabeth S.; Monks, Anne; Watkins, Simon C.; Wang, Anne S.; Lazo, John S.

doi:10.1007/s002800050708

Cited by 40 publications

(15 citation statements)

References 21 publications

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“…The potential for basal levels of endogenous (e.g., oxidative) stress, associated with abnormal zinc availability (14), to exert any cell cycle disturbing effects will depend not only on the availability of protective mechanisms for a given type of stress, but also on the ability of the cellular system to enact a cell cycle-linked response. In general, it appears that cytoplasmic MT protects against cytotoxicity, whereas nuclear MT protects against genotoxicity (1,2,8,40,57,58). Our distribution study indicated a primarily cytoplasmic location for enforced MT-1 overexpression.…”

Section: Discussionmentioning

confidence: 48%

Impact of overexpression of metallothionein-1 on cell cycle progression and zinc toxicity

Smith

Wiltshire²,

Furon³

et al. 2008

American Journal of Physiology-Cell Physiology

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Metallothioneins (MTs) have an important role in zinc homeostasis and may counteract the impact of oversupply. Both intracellular zinc and MT expression have been implicated in proliferation control and resistance to cellular stress, although the interdependency is unclear. The study addresses the consequences of a steady-state overexpression of MT-1 for intracellular zinc levels, cell cycle progression, and protection from zinc toxicity using a panel of cell lines with differential expression of MT-1. The panel comprised parental Chinese hamster ovary-K1 cells with low endogenous expression of MT and transfectants with enhanced expression of mouse MT-1 on an autonomously replicating expression vector with a noninducible promoter. Cell cycle progression, determined by flow cytometry and time-lapse microscopy, revealed that enhanced cytoplasmic expression of MT-1 does not impact on normal cell cycle operation, suggesting that basal levels of MT-1 expression are not limiting for background levels of oxidative stress. MT-1 overexpression correlated with a steady-state increase in cytoplasmic free Zn(2+), assessed using the fluorescent zinc-sensor Zinquin, particularly at high levels of overexpression, further suggesting that zinc availability is normally not limiting for cell cycle progression. Enhanced MT-1 expression, over a 10-fold range, had a clear impact on resistance to Cd(2+) and Zn(2+) toxicity. In the case of Zn(2+), the degree of protection afforded was less, indicating that MT-1 has a limited range and saturable capacity for effecting resistance. The results have implications for the use of cellular stress responses to exogenously supplied zinc and zinc-based systemic therapies.

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Section: Discussionmentioning

confidence: 48%

Impact of overexpression of metallothionein-1 on cell cycle progression and zinc toxicity

Smith

Wiltshire²,

Furon³

et al. 2008

American Journal of Physiology-Cell Physiology

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“…Likewise, MT levels were also significantly increased in patients not responding to cisplatin and carboplatin treatment [79]. Moreover, in cultures of malignat cells MT levels are often significantly increased resulting in an even stronger Pt II scavenging effect [77,[80][81][82]. MT expression during cancer development was addressed for various malignant cells and tissues [83] where the degree of MT expression and the influence on cancer development showed a strong diversity among the investigated types of tissue and cells [81,84].…”

Section: Metallothionein and Platinum Treatmentmentioning

confidence: 99%

Metallothioneins and Platinum(II) Anti-Tumor Compounds

Knipp

2009

CMC

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The classical square planar transition metal complex cis-diamminodichlorido platinum(II) (cisplatin) ranks among the most successful and widely applied antitumor drugs for the treatment of a number of cancers. However, the risk of unforeseen resistance formation and the appearance of severe side effects in cancer patients constitutes a considerable need for the development of novel platinum based antitumor compounds. Since the introduction of cisplatin into the clinic, a few similar compounds, like cis-diammine(1,1-cyclobutanedicarboxylato)platinum(II) (carboplatin), were developed, which can partly overcome the problems. The ubiquitously occurring small zinc and copper binding proteins metallothioneins (MTs) constitute the most potent cytosolic sink for platinum drugs. It appeared that, besides the formation of the very strong platinum(II)-sulfur bond involving the twenty cysteine residues of MT, the incorporation of platinum(II) into the MT structure contributes effectively to the scavenging of the drug. However, recently it became evident that the extent, to which MT sequesters platinum drugs, depends not only on the type of cancer, but also on the interaction of MT with the ligand sphere of the platinum center. For example, in contrast to cis-platinum(II) compounds, trans-platinum(II) compounds retain their N-donor ligands upon reaction with MT. From these studies, guidelines may be derived for the development of N-donor carrier ligands leading to novel platinum(II) drugs. This review describes the role of metallothioneins for the platinum(II) drug sequestration in vivo. Furthermore, it summarizes the recent developments toward the understanding of the reaction between platinum(II) and MT thiols and the structural aspects of the platinum(II) incorporation into the MT domains, and comments about future perspectives are given.

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“…Thus, in the same cell line, physiological changes of the glutathione redox potential affect the redox state of MT and the amount of "free" zinc, clearly linking the availability of zinc, MT, and redox metabolism. Many factors induce MT expression and thereby alter the zinc and redox buffering capacity; the protein varies at least 400-fold in different cell lines (23). The protein that is induced, however, is thionein, not metallothionein.…”

Section: Cellular Zinc Buffering Capacity and "Free" Zincmentioning

confidence: 99%

Cellular Zinc and Redox Buffering Capacity of Metallothionein/Thionein in Health and Disease

Maret

Krężel

2007

Mol Med

167

132

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Zinc is involved in virtually all aspects of cellular and molecular biology as a catalytic, structural, and regulatory cofactor in over 1000 proteins. Zinc binding to proteins requires an adequate supply of zinc and intact molecular mechanisms for redistributing zinc ions to make them available at the right time and location. Several dozen gene products participate in this process, in which interactions between zinc and sulfur donors determine the mobility of zinc and establish coupling between cellular redox state and zinc availability. Specifically, the redox properties of metallothionein and its apoprotein thionein are critical for buffering zinc ions and for controlling fluctuations in the range of picomolar concentrations of "free" zinc ions in cellular signaling. Metallothionein and other proteins with sulfur coordination environments are sensitive to redox perturbations and can render cells susceptible to injury when oxidative stress compromises the cellular redox and zinc buffering capacity in chronic diseases. The implications of these fundamental principles for zinc metabolism in type 2 diabetes are briefly discussed.

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Diversity of metallothionein content and subcellular localization in the National Cancer Institute tumor panel

Abstract: These results demonstrated significant diversity in MT content and subcellular localization in human tumor cells. Moreover, both basal MT levels and subcellular distribution appeared to be determinants of cellular responsiveness to metal-containing compounds.

Cited by 40 publications

References 21 publications

Impact of overexpression of metallothionein-1 on cell cycle progression and zinc toxicity

Impact of overexpression of metallothionein-1 on cell cycle progression and zinc toxicity

Metallothioneins and Platinum(II) Anti-Tumor Compounds

Cellular Zinc and Redox Buffering Capacity of Metallothionein/Thionein in Health and Disease

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