p53 activation by Ni(II) is a HIF-1α independent response causing caspases 9/3-mediated apoptosis in human lung cells

Abstract

Hypoxia mimic nickel(II) is a human respiratory carcinogen with a suspected epigenetic mode of action. We examined whether Ni(II) elicits a toxicologically significant activation of the tumor suppressor p53, which is typically associated with genotoxic responses. We found that treatments of H460 human lung epithelial cells with NiCl2 caused activating phosphorylation at p53-Ser15, accumulation of p53 protein and depletion of its inhibitor MDM4 (HDMX). Confirming activation of p53, its knockdown suppressed the ability of Ni(II) to upregulate MDM2 and p21 (CDKN1A). Unlike DNA damage, induction of GADD45A by Ni(II) was p53-independent. Ni(II) also increased p53-Ser15 phosphorylation and p21 expression in normal human lung fibroblasts. Although Ni(II)-induced stabilization of HIF-1α occurred earlier, it had no effect on p53 accumulation and Ser15 phosphorylation. Ni(II)-treated H460 cells showed no evidence of necrosis and their apoptosis and clonogenic death were suppressed by p53 knockdown. The apoptotic role of p53 involved a transcription-dependent program triggering the initiator caspase 9 and its downstream executioner caspase 3. Two most prominently upregulated proapoptotic genes by Ni(II) were PUMA and NOXA but only PUMA induction required p53. Knockdown of p53 also led to derepression of antiapoptotic MCL1 in Ni(II)-treated cells. Overall, our results indicate that p53 plays a major role in apoptotic death of human lung cells by Ni(II). Chronic exposure to Ni(II) may promote selection of resistant cells with inactivated p53, providing an explanation for the origin of p53 mutations by this epigenetic carcinogen.

The effect of metallothionein 2A core promoter region single-nucleotide polymorphism on accumulation of toxic metals in sinonasal inverted papilloma tissues

“…An increasing body of evidence indicates that heavy metals and metallic agents may play an important role in tumorigenesis, but direct functional connections with MT2A gene activity, and thus toxicity of metallic elements, remains poorly defined (Ahamed and Alhadlaq, 2014;Akinmoladun et al, 2013;Crisponi, 2014;Rehman and Husnain, 2014;Qiao et al, 2014;Wong et al, 2013). The importance of the relationship between MT2A SNP and aberrant expression of heavy and toxic metals in malignant or benign tumors has been investigated in only a few studies and the relationship itself remains largely unknown.…”

“…Numerous studies have suggested that exposure to nickel soluble and particulate forms may have a carcinogenic potential on the airway epithelium (Ahamed et al, 2014;Forti et al, 2011;Pietruska et al, 2011;Tokar et al, 2011;Wong et al, 2013). A considerable body of evidence exists of the genotoxic and mutagenic activity of Ni ions in human epithelial cells, but the exact mechanisms of nickelinduced tumorigenesis remain poorly understood.…”

“…A considerable body of evidence exists of the genotoxic and mutagenic activity of Ni ions in human epithelial cells, but the exact mechanisms of nickelinduced tumorigenesis remain poorly understood. The data indicates that intracellular Ni activates multiple signaling pathways that may contribute to cytotoxicity and promote cell transformation and tumor progression (Ahamed and Alhadlaq, 2014;Forti et al, 2011;Pietruska et al, 2011;Wong et al, 2013). However, other researchers report contradictory findings on the ability of Ni to be implicated in human tumor biology and introduce no implication of nickel compounds for tumorigenesis and respiratory cancer risk (Krześlak et al, 2013;Sivulka and Seilkop, 2009).…”

“…Many heavy metals, metallic agents and their compounds have biological activity and potential or proven carcinogenicity in humans (Ahamed and Alhadlaq, 2014;Crisponi, 2014;Tokar et al, 2011;Qiao et al, 2014;Wong et al, 2013). Exposure to these inorganics in the form of free ions, metal complexes, metal particles and poorly-soluble compounds occurs most often during inhalation from environmental and occupational sources at workplaces and through ingestion.…”

“…Qiao et al, 2014;Tokar et al, 2011;Wong et al, 2013). The conversion of nucleotide A to G in the core promoter region of the MT2A gene may reduce the effectiveness of MT gene transcription induced by metallic agents or toxic metals, which may consequently lead to an increase in sensitivity to metal toxicity, and may enable the use of MT issue in evaluating the risk of tumors of various origin(Forma et al, 2012;Kita et al, 2006;Krześlak et al, 2014Krześlak et al, , 2013Mehus et al, 2014;Pedersen et al, 2009).…”