Selenium activates p53 and p38 pathways and induces caspase-independent cell death in cervical cancer cells

Kao²,

et al. 2012

J. Toxicol. Sci.

-NO plays an important role in cartilage destruction by inducing apoptosis of chondrocytes. Here we investigated the role of c-Jun N-terminal kinase (JNK) signal transduction pathways in the apoptosis induced by NO donor sodium nitroprusside (SNP) in rabbit articular chondrocytes. We used Annexin V-FITC/PI flow cytometry and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay (TUNEL) assay to detect apoptosis rate. The expressions of p38, NF-κB p65, caspase-3 and p53 genes at protein levels were measured by Western blotting assay. RT-PCR was performed to show the mRNA expression of caspase-3, and the activity of caspase-3 was also detected. To investigate the effect of JNK-specific inhibitor SP600125, chondrocytes were pretreated with SP600125 ahead of SNP treatment. Treatment with SNP accelerated apoptosis in a concentration dependent manner, while such acceleration was reduced by SP600125 pretreatment. Moreover, we found that SP600125 significantly decreased NO-induced NF-κB, p53, caspase-3 protein expressions and caspase-3 mRNA expression, as well as intracellular caspase-3 activity (P < 0.05). Collectively, these data suggest that JNK plays an important role through stimulating NF-κB, p53 and caspase-3 activation.

Section: Introductionmentioning

confidence: 99%

SNP-induced apoptosis may be mediated with caspase inhibitor by JNK signaling pathways in rabbit articular chondrocytes

Kao²,

et al. 2012

J. Toxicol. Sci.

Proc. Natl. Acad. Sci. U.S.A.

“…A major mechanism of selenite cytotoxicity is thought to be the generation of oxidative stress through intracellular redox cycling of the selenium metabolite selenide with oxygen and cellular thiols, producing nonstoichiometric amounts of superoxide and cellular disulfides. The induction of oxidative stress and consequent apoptosis has been demonstrated in numerous cancer cell lines (2)(3)(4)(5)(6)(7)(8), but why this occurs only in malignant cells at easily achievable selenium plasma concentrations remains unclear.…”

mentioning

confidence: 99%

Extracellular thiol-assisted selenium uptake dependent on the x _c ⁻ cystine transporter explains the cancer-specific cytotoxicity of selenite

Olm

Fernandes²,

Hebert³

et al. 2009

149

120

The selenium salt selenite (SeO3 2؊ ) is cytotoxic in low to moderate concentrations, with a remarkable specificity for cancer cells resistant to conventional chemotherapy. Our data show that selenium uptake and accumulation, rather than intracellular events, are crucial to the specific selenite cytotoxicity observed in resistant cancer cells. We show that selenium uptake depends on extracellular reduction, and that the extracellular environment is a key factor specific to selenite cytotoxicity. The extracellular reduction is mediated by cysteine, and the efficacy is determined by the uptake of cystine by the x c ؊ antiporter and secretion of cysteine by multidrug resistance proteins, both of which are frequently overexpressed by resistant cancer cells. This mechanism provides molecular evidence for the existence of an inverse relationship between resistance to conventional chemotherapy and sensitivity to selenite cytotoxicity, and highlights the great therapeutic potential in treating multidrug-resistant cancer.2Ϫ ) efficiently inhibits the growth of malignant cells and studies suggest an inverse relationship between resistance to cytotoxic drugs and sensitivity to selenite (SeO 3 2Ϫ ) (1, 2). A major mechanism of selenite cytotoxicity is thought to be the generation of oxidative stress through intracellular redox cycling of the selenium metabolite selenide with oxygen and cellular thiols, producing nonstoichiometric amounts of superoxide and cellular disulfides. The induction of oxidative stress and consequent apoptosis has been demonstrated in numerous cancer cell lines (2-8), but why this occurs only in malignant cells at easily achievable selenium plasma concentrations remains unclear.With the assumption that the mechanistic explanation is intracellular, studies on differences in cellular uptake have been neglected. Already in the 1960s, selenite (SeO 3 2Ϫ ) was being used experimentally as a tumor-localizing agent. Neoplasms could be detected in brain and thorax in human subjects through i.v. administration of radioactive selenite ( 75 Se) (9). Although at that time the cancer-specific cytotoxic effects of selenite were unknown, and low doses were used (approximately in the nM range in blood) (9), early findings clearly demonstrated that cancer cells enrich selenium in vivo. These findings, combined with current knowledge of selenite's toxic effects on malignant cells, raise the possibility of a cancer-specific high-affinity selenium uptake mechanism that might explain cancer-specific selenite cytotoxicity at therapeutic selenite concentrations (M range).In yeast, millimolar tolerance to selenite can be reduced to the micromolar range by the presence of excessive thiols in the growth medium through high-affinity uptake of a more reduced form of selenite, possibly selenide (10). High-affinity uptake of selenium through the addition of extracellular thiols also has been demonstrated in a keratinocyte model (11) using nanomolar concentrations of selenite. Selenium uptake was prevented in keratinocytes by the ...

“…Additional mechanisms might be prooxidant and mitochondrial damage, particularly for species such as Se-IV, Se-VI, and Se-Met [26,34,35,36], copper/zinc superoxide-dismutase translocation into mitochondria, and increased inducible nitric oxide synthase [37], DNA damage [38], and P38-P53 activation [39]; all mechanisms are potentially involved in ALS etiopathogenesis [3,40], and more generally functional alterations due to nonspecific incorporation of selenium species into proteins and to adverse effects on lipid metabolism and protein synthesis [41]. …”

Section: Discussionmentioning

confidence: 99%

Elevated Levels of Selenium Species in Cerebrospinal Fluid of Amyotrophic Lateral Sclerosis Patients with Disease-Associated Gene Mutations

Mandrioli¹,

Michalke

Solovyev

et al. 2017

Neurodegener Dis

Background: Although an increasing role of genetic susceptibility has been recognized, the role of environmental risk factors in amyotrophic lateral sclerosis (ALS) etiology is largely uncertain; among neurotoxic chemicals, epidemiological and biological plausibility has been provided for pesticides, the heavy metal lead, the metalloid selenium, and other persistent organic pollutants. Selenium involvement in ALS has been suggested on the basis of epidemiological studies, in vitro investigations, and veterinary studies in which selenium induced a selective toxicity against motor neurons. Objective: Hypothesizing a multistep pathogenic mechanism (genetic susceptibility and environmental exposure), we aimed to study selenium species in ALS patients carrying disease-associated gene mutations as compared to a series of hospital controls. Methods: Using advanced analytical techniques, we determined selenium species in cerebrospinal fluid sampled at diagnosis in 9 ALS patients carrying different gene mutations (C9ORF72, SOD1, FUS, TARDBP, ATXN2, and TUBA4A) compared to 42 controls. Results: In a patient with the tubulin-related TUBA4A mutation, we found highly elevated levels (in μg/L) of glutathione-peroxidase-bound selenium (32.8 vs. 1.0) as well as increased levels of selenoprotein-P-bound selenium (2.4 vs. 0.8), selenite (1.8 vs. 0.1), and selenate (0.9 vs. 0.1). In the remaining ALS patients, we detected elevated selenomethionine-bound selenium levels (0.38 vs. 0.06). Conclusions: Selenium compounds can impair tubulin synthesis and the cytoskeleton structure, as do tubulin-related gene mutations. The elevated selenium species levels in the TUBA4A patient may have a genetic etiology and/or represent a pathogenic pathway through which this mutation favors disease onset, though unmeasured confounding cannot be excluded. The elevated selenomethionine levels in the other patients are also of interest due to the toxicity of this nonphysiological selenium species. Our study is the first to assess selenium exposure in genetic ALS, suggesting an interaction between this environmental factor and genetics in triggering disease onset.