Zinc induced apoptosis in HEP-2 cancer cells: The role of oxidative stress and mitochondria

Rudolf, Emil; Rudolf, Kamil; Červinka, Miroslav

doi:10.1002/biof.5520230206

Cited by 45 publications

(36 citation statements)

References 30 publications

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“…However, contrasting data are reported in literature, particularly on the effects of zinc on apoptosis. We assume that such discrepancies may be related, at least in part, to the wide range of zinc concentrations used in different studies (Truong-Tran et al 2000;Nodera et al 2001;Lambert et al 2001;Schrantz et al 2001;Rudolf et al 2005). In this context, we report in the present study that physiological concentration of zinc ions (12.5 lM) affects in vitro both spontaneous and oxidative stress-induced apoptosis.…”

Section: Discussioncontrasting

confidence: 48%

Effect of zinc ions on apoptosis in PBMCs from healthy aged subjects

et al. 2006

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Immunosenescence features, such as thymic involution, alteration of T-cell repertoire, autoimmunity and accumulation of memory/effector T cells, may be the result, at least in part, of a zinc deficiency, which is often observed during ageing. Zinc, as essential trace element, affects the immune system function and it is an important regulator of apoptosis of immune cells. In this study we addressed the question whether zinc supplementation in vitro at physiological doses can affect spontaneous and oxidative stress-induced apoptosis in peripheral blood mononuclear cells from subjects of three different age groups: young (mean age 28 years), old (mean age 72 years) and nonagenarians. We studied different parameters related to apoptosis (phosphatydilserine exposure, mitochondrial membrane potential, caspase 3 cleavage) and we found that zinc, while decreasing spontaneous apoptosis, can increase oxidative stress-induced apoptosis in an age-related fashion, being this effect more evident in nonagenarians than in old or young subjects. In particular, zinc can increase late apoptosis/necrosis, a phenomenon that could trigger unnecessary inflammation in vivo. We surmise that these age-associated alterations in susceptibility to apoptosis may be due to a different effect of zinc on T cell subsets, that are altered in very old people, and finally that the zinc deficiency, which is often observed in aged subjects, could be a compensatory mechanism to counteract the inflammatory status of the elderly.

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Section: Discussioncontrasting

confidence: 48%

Effect of zinc ions on apoptosis in PBMCs from healthy aged subjects

et al. 2006

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“…Similarly, zinc replenishment in rats rapidly induces apoptosis in esophageal epithelial cells and substantially reduces the development of tumors; and the treatment increases the level of Bax [40]. Rudolf et al [48] reported that zinc acts both directly and indirectly on mitochondria to induce apoptosis in HEP-2 cancer cells. Bae et al [47] also determined the effect of zinc treatment of human epithelial ovarian cancer cells on the maconitase activity.…”

Section: Tumor Suppressor Effects Of Zinc In Other Tumor Cellsmentioning

confidence: 99%

Zinc as an anti-tumor agent in prostate cancer and in other cancers

Franklin¹,

Costello²

2007

Archives of Biochemistry and Biophysics

211

142

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Human prostate glandular epithelial cells have the unique capability of accumulating high levels of zinc. This is essential to inhibit m-aconitase activity so that citrate can accumulate for secretion into prostatic fluid, which is a major function of the prostate gland. As a result, the Krebs cycle is truncated with the consequence of the lost ATP production that would result from citrate oxidation. The cellular accumulation of zinc also inhibits mitochondrial terminal oxidation and respiration. In addition to these metabolic effects, zinc accumulation exhibits anti-proliferative effects via its induction of mitochondrial apoptogenesis. Zinc accumulation also inhibits the invasive/migration activities in malignant prostate cells. The anti-proliferative effects and the effects on invasion and migration occur through zinc activation of specific intracellular signaling pathways. Consequently, these effects impose anti-tumor actions by zinc. The ability of prostate cells to accumulate zinc is due to the expression and activity of the zinc uptake transporter, ZIP1. To avoid the anti-tumor effects of zinc, in prostate cancer the malignant prostate cells exhibit a silencing of ZIP1 gene expression accompanied by a depletion of cellular zinc. Therefore we regard ZIP1 as a tumor suppressor gene in prostate cancer. In addition to prostate cells, similar tumor suppressor effects of zinc have been identified in several other types of tumors. KeywordsZinc; prostate cancer; tumor suppressor; apoptosis; Krebs cycle; zinc transporter; intermediary metabolismThe physiology and biochemistry of zinc and its importance in normal cellular and bodily function has been the subject of numerous reviews [1][2][3][4]. The regulation and maintenance of a "normal" concentration and distribution of cellular zinc are essential to the function, metabolism, growth, proliferation and survival of cells. A significant clinical aspect of zinc is its role in the development and progression of malignancy. There is now compelling clinical and experimental evidence that zinc is an important factor in prostate cancer, and also in other types of cancer. In relation to essential tumor cell activities, the effects of zinc can be categorized as: intermediary metabolism and bioenergetics effects; motility and invasive effects; growth and proliferation effects. The actions of zinc on all three activities impose antitumor effects in malignant prostate cells and other tumor cells. This review will present the *Correspondence to: Renty B.

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“…The fact that free zinc levels did not dwindle at later treatment periods indicate that the speed and extent of incoming zinc pools was clearly exhaustive for any homeostatic mechanisms the cells might otherwise have employed, thereby establishing a situation which might better reflect real conditions within an organism. From our previous experiments we know that in Hep-2 cells zinc induces apoptosis, which is characterized by the involvement of oxidative stress, p53 and mitochondria, and which is executed both caspase-dependently and -independently (15). Hence we wanted to know more details about the role of p53 in this process and, namely, to explore a mechanism whereby this protein could be activated.…”

Section: Discussionmentioning

confidence: 99%

“…In our recent work we discovered that treatment of Hep-2 cells with external zinc during 96 h induces p53-dependent as well as -independent apoptosis (15). To verify the involvement of p53 in cell injury and apoptosis of Hep-2 cells subacutely exposed to external zinc during 24 h, we employed Pifithrin-α, a specific p53 inhibitor, and determined the rate of apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…In our previous report we showed that externally supplied zinc induces cell injury and apoptosis in Hep-2 cells during 96 h of treatment, in particular by means of oxidative stress, activation of p53 pathway as well as via direct zinc effect on mitochondria (15). Presently, we wanted to investigate the effect of subacute zinc exposure on Hep-2 cells viability while focusing on putative involvement of MAPK cascades and their functional linkage with p53-dependent signaling.…”

Section: Introductionmentioning

confidence: 99%

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Increased Uptake of Zinc in Malignant Cells is Associated with Enhanced Activation of MAPK Signalling and P53-Dependent Cell Injury

Rudolf

2008

Acta Med. (Hradec Kralove, Czech Repub.)

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Summary:Excess intracellular zinc has been demonstrated to be responsible for cell injury and cell death in various experimental as well as clinical models. While the cells possess a system of mechanisms regulating intracellular zinc homeostasis, their saturation by acutely increased zinc levels or by a sustained exposure to elevated zinc levels results in liberation of free zinc stores within the cells and ultimate cell damage and cell death. Here we report that in Hep-2 malignant cells enhanced uptake of zinc causes activation of mitogen-activated protein kinase (MAPK) signaling with resulting p53-dependent cell injury which can be significantly prevented by specific p53 inhibition and by prevention of oxidative stress. Our observations are consistent with the view that subacutely increased intracellular free zinc levels stimulate via oxidative stress p53-dependent pathways which are responsible for the final cell damage in tumor cells.

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Zinc induced apoptosis in HEP-2 cancer cells: The role of oxidative stress and mitochondria

Cited by 45 publications

References 30 publications

Effect of zinc ions on apoptosis in PBMCs from healthy aged subjects

Effect of zinc ions on apoptosis in PBMCs from healthy aged subjects

Zinc as an anti-tumor agent in prostate cancer and in other cancers

Increased Uptake of Zinc in Malignant Cells is Associated with Enhanced Activation of MAPK Signalling and P53-Dependent Cell Injury

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