Vitamin D sensitizes breast cancer cells to the action of H2O2: Mitochondria as a convergence point in the death pathway

Weitsman, Gregory; Koren, Ruth; Zuck, Efrat; Rotem, Carmela; Liberman, Uri; Ravid, Amiram

doi:10.1016/j.freeradbiomed.2005.03.018

Cited by 45 publications

(39 citation statements)

References 49 publications

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“…A feature shared by these agents is their ability to bring about excessive reactive oxygen species (ROS) generation in their target cells, suggesting that the crosstalk between the hormone and these agents is a ROSdependent process. This notion was strongly supported by our recent finding that calcitriol sensitizes human breast cancer cells to H 2 O 2 [23].…”

Section: Introductionsupporting

confidence: 63%

“…Comparison to previous findings reveals that this activity is only around 10% of caspase-3-like activity observed in MCF-7 cells under similar conditions [23]. The dose-response curve of caspase activation in response to H 2 O 2 is depicted in Fig.…”

Section: The Effect Of Calcitriol On the Activation Of Executioner Casupporting

confidence: 55%

“…We have previously observed in other experimental systems that 1-h exposure of MCF-7 breast cancer cells or HaCaT keratinocytes to H 2 O 2 at concentrations of 0.5-1 mM induced significant caspase activity 4-20 h after removal of the oxidant [23,38]. Although there is no detectable cytotoxicity resulting from exposure of HT-29 cells to H 2 O 2 at that concentration range (Fig.…”

Section: The Effect Of Calcitriol On the Activation Of Executioner Camentioning

confidence: 68%

“…In 11 independent experiments the cytotoxic effect of H 2 O 2 at a concentration of 15 mM was 33 ± 3% ranging between 20% and 48%. Notably, these cells seem to be much more resistant to the oxidative challenge than other tumor cells, such as MCF-7 human breast cancer cells where significant cell death was observed in cultures exposed to 0.2 mM H 2 O 2 under identical conditions [23]. Staining of H 2 O 2 -treated HT-29 cells with propidium iodide and Hoechst 33342 revealed that cell death is accompanied by chromatin condensation that precedes the disruption of membrane integrity as evidenced by propidium iodide staining (Fig.…”

Section: The Effect Of Calcitriol On H 2 O 2 -Induced Death Of Ht-29 mentioning

confidence: 99%

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Calcitriol sensitizes colon cancer cells to H2O2-induced cytotoxicity while inhibiting caspase activation

Koren

Wacksberg

Weitsman

et al. 2006

The Journal of Steroid Biochemistry and Molecular Biology

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Section: Introductionsupporting

confidence: 63%

Section: The Effect Of Calcitriol On the Activation Of Executioner Casupporting

confidence: 55%

Section: The Effect Of Calcitriol On the Activation Of Executioner Camentioning

confidence: 68%

Section: The Effect Of Calcitriol On H 2 O 2 -Induced Death Of Ht-29 mentioning

confidence: 99%

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Calcitriol sensitizes colon cancer cells to H2O2-induced cytotoxicity while inhibiting caspase activation

Koren

Wacksberg

Weitsman

et al. 2006

The Journal of Steroid Biochemistry and Molecular Biology

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“…Therefore, it is possible that exercise may support BDNF-mediated synaptic plasticity by limiting OS to increase the efficiency of energy production from mitochondria. It is likely that physical activity achieves this capacity through the mitochondrion, as D3 acts to disrupt mitochondrial metabolism (Weitsman et al, 2003) by increasing free radical cytotoxicity to affect mitochondrial membrane potential (Weitsman et al, 2005). In fact, we found that D3 infusion prevented the ability of exercise to limit OS ( Fig.…”

Section: Exercise Decreases Os: Mechanisms To Maintain Homeostasismentioning

confidence: 66%

Coupling energy metabolism with a mechanism to support brain-derived neurotrophic factor-mediated synaptic plasticity

Vaynman¹,

Ying²,

Wu³

et al. 2006

Neuroscience

141

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Abstract-Synaptic plasticity and behaviors are likely dependent on the capacity of neurons to meet the energy demands imposed by neuronal activity. We used physical activity, a paradigm intrinsically associated with energy consumption/ expenditure and cognitive enhancement, to study how energy metabolism interacts with the substrates for neuroplasticity. We found that in an area critical for learning and memory, the hippocampus, exercise modified aspects of energy metabolism by decreasing oxidative stress and increasing the levels of cytochrome c oxidase-II, a specific component of mitochondrial machinery. We infused 1,25-dihydroxyvitamin D3, a modulator of energy metabolism, directly into the hippocampus during 3 days of voluntary wheel running and measured its effects on brain-derived neurotrophic factormediated synaptic plasticity. Brain-derived neurotrophic factor is a central player for the effects of exercise on synaptic and cognitive plasticity. We found that 25-dihydroxyvitamin D3 decreased exercise-induced brain-derived neurotrophic factor but had no significant effect on neurotrophin-3 levels, thereby suggesting a level of specificity for brain-derived neurotrophic factor in the hippocampus. 25-Dihydroxyvitamin D3 injection also abolished the effects of exercise on the consummate end-products of brain-derived neurotrophic factor action, i.e. cyclic AMP response element-binding protein and synapsin I, and modulated phosphorylated calmodulin protein kinase II, a signal transduction cascade downstream to brain-derived neurotrophic factor action that is important for learning and memory. We also found that exercise significantly increased the expression of the mitochondrial uncoupling protein 2, an energy-balancing factor concerned with ATP production and free radical management. Our results reveal a fundamental mechanism by which key elements of energy metabolism may modulate the substrates of hippocampal synaptic plasticity.

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1,25‐Dihydroxyvitamin D₃ enhances NK susceptibility of human melanoma cells via Hsp60‐mediated FAS expression

et al. 2011

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The active metabolite of vitamin D 3 , 1a,25(OH) 2 D 3 , displays anticancer effects by regulating cell cycle and apoptosis in many cancer cells. However, it has not been determined whether 1a,25(OH) 2 D 3 increases the susceptibility of cancer cells to NK cells. Here, we investigated the anticancer effect of 1a,25(OH) 2 D 3 in human melanoma cell lines by investigating enhancement of NK susceptibility and elucidating the mediator of NK cytotoxicity. 1a,25(OH) 2 D 3 -resistant melanoma cells (G-361 and SK-MEL-5) treated with 1a,25(OH) 2 D 3 showed higher susceptibility to NK cells with up-regulation of Fas expression. Furthermore, G-361 cells treated with 1a,25(OH) 2 D 3 showed significantly increased caspase activity. In addition to Fas up-regulation, expression of heat shock protein 60 (Hsp60) was elevated by 1a,25(OH) 2 D 3 . Increased expression of Hsp60 by 1a,25(OH) 2 D 3 was related to not only up-regulation of Fas expression but also to NK susceptibility of G-361 cells. Taken together, our data suggest that 1a,25(OH) 2 D 3 acts as an anticancer agent by increasing expression of Fas on the surface of melanoma cells through Hsp60 induction and strengthens caspase sensitivity to Fas-mediated apoptotic pathway by NK cells. 1a,25(OH) 2 D 3 treatment may therefore have a preventive role in melanoma occurrence or potentiate the anticancer effects of NK-cell immune therapy. Heat shock proteins (HSPs) are evolutionarily conserved proteins induced by cell stress such as heat, oxidative stress, and hypoxia [21]. HSPs are molecular chaperones that are classified into families according to their molecular weight and function as chaperones [22]. HSPs have multiple functions in gene expression, DNA replication, signal transduction, and apoptosis [23]. Hsp60 is a mitochondrial protein known to assist protein folding in prokaryotes and eukaryotes [24]. Hsp60 is also found in cytoplasm, and both forms of Hsp60 can function in pro-survival or pro-apoptotic pathways, depending on the cell type [25]. It is reported that Hsp60 may trigger apoptosis through caspase cascade activation via an association between Hsp60/Hsp10 complex and pro-caspase-3 [26]. Although Hsp60 plays important roles in various biological events, the exact molecular roles of Hsp60 in melanoma are poorly understood, and the relationship between 1a,25(OH) 2 D 3 and Hsp60 has not been reported.In 2938that on cancer cells, Fas delivers an apoptotic signal after engagement of Fas ligand on NK cells [15]. Additionally, ULBP2 and MICA/B are known ligands for NK-activating receptor, NKG2D[30]. Among those molecules tested, the expression of Fas was increased by 1a,25(OH) 2 D 3 treatment in G-361 and SK-MEL-5 cells ( Fig. 2A). However, the expression of ULBP2 and MICA/B was not increased by 1a,25(OH) 2 D 3 (data not shown). The expression of Fas showed maximum level at 72 h incubation (M1 gated 5 51.370.9% compared to 37.571.7% in control) (Fig. 2B). mRNA expression of Fas also increased following treatment with 1a,25(OH) 2 D 3 (1.9-fold) (Fig. 2C). From these d...

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Vitamin D sensitizes breast cancer cells to the action of H2O2: Mitochondria as a convergence point in the death pathway

Cited by 45 publications

References 49 publications

Calcitriol sensitizes colon cancer cells to H2O2-induced cytotoxicity while inhibiting caspase activation

Calcitriol sensitizes colon cancer cells to H2O2-induced cytotoxicity while inhibiting caspase activation

Coupling energy metabolism with a mechanism to support brain-derived neurotrophic factor-mediated synaptic plasticity

1,25‐Dihydroxyvitamin D₃ enhances NK susceptibility of human melanoma cells via Hsp60‐mediated FAS expression

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Vitamin D sensitizes breast cancer cells to the action of H2O2: Mitochondria as a convergence point in the death pathway

Cited by 45 publications

References 49 publications

Calcitriol sensitizes colon cancer cells to H2O2-induced cytotoxicity while inhibiting caspase activation

Calcitriol sensitizes colon cancer cells to H2O2-induced cytotoxicity while inhibiting caspase activation

Coupling energy metabolism with a mechanism to support brain-derived neurotrophic factor-mediated synaptic plasticity

1,25‐Dihydroxyvitamin D3 enhances NK susceptibility of human melanoma cells via Hsp60‐mediated FAS expression

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1,25‐Dihydroxyvitamin D₃ enhances NK susceptibility of human melanoma cells via Hsp60‐mediated FAS expression