Cadmium-Associated Molecular Signatures in Cancer Cell Models

Version	Summary	Created by	Modification	Content Size	Created at	Operation
1		Claudio Luparello	--	3317	2023-07-12 08:43:40	\|
2	format change	Peter Tang	Meta information modification	3317	2023-07-12 09:35:09	\|

This entry is adapted from the peer-reviewed paper 10.3390/cancers13112823

The exposure of cancer cells to cadmium and its compounds is often associated with the development of more malignant phenotypes, thereby contributing to the acceleration of tumor progression. It is known that cadmium is a transcriptional regulator that induces molecular reprogramming, and therefore the study of differentially expressed genes has enabled the identification and classification of molecular signatures inherent in human neoplastic cells upon cadmium exposure as useful biomarkers that are potentially transferable to clinical research.

cadmium differential expression gene signature in vitro cell models breast cancer gastric cancer colon cancer liver cancer lung cancer nasopharyngeal cancer

1. Introduction: A Short Excursus on Cadmium and Eukaryotic Cell Systems

Cadmium (Cd) is an underground mineral extracted as part of zinc deposits which, along with its compounds, exhibits a broad range of applications in the industry spanning from battery components to stabilizers for plastics, electroplated coatings for non-ferrous metals and dye pigments. Volcanic eruption and the erosion of Cd-containing rocks represent the major natural sources of the metal; on the other hand, humans are mainly exposed to Cd via cigarette smoking and, to a lesser extent, food ingestion, inhalation of polluted air, and the ingestion of contaminated drinking water ^[1].

Cd is not essential for the human body and does not exert any useful cellular metabolic effect. The cellular uptake of free Cd ions and complexes of Cd with small organic molecules involves various ion channels, carriers, and ATPase pumps, whereas Cd-protein complexes are internalized via receptor-mediated endocytosis, as extensively reviewed by the authors in ^[2]. Once accumulated in the intracellular milieu, the metal may interact with the thiol groups of cysteines present in cellular proteins, thus inducing an impairment of the functions of the enzymes located in different cellular compartments. The numerous biological targets and complex mechanisms of the action of Cd ions have been explored in depth in previously-published reviews ^[3]^[4]^[5]. It is known that Cd can cause mitochondrial dysfunction, exert genotoxic and epigenotoxic effects, and can also interfere with a number of cell proliferation-linked signalization pathways. Reports in the literature have shown that mitochondria are one of the main intracellular targets for Cd toxicity due to the blocking of the electron transfer chain at complex III, which is considered the principal site for the production of reactive oxygen species (ROS), thereby favoring the over-production of the latter at the expense of ATP. This leads to a dissipation of mitochondrial transmembrane potential with a consequent alteration of not only the cell’s redox status but also mitochondrial and nuclear gene expression and the genome integrity ^[6]^[7]. In fact, it is widely acknowledged that the genome-related effects of Cd are based upon its ability to damage the antioxidant defense and DNA repair systems, and also due to the replacement of zinc by Cd in p53 with a consequent impairment of protein activity, thereby triggering the occurrence of DNA strand breaks and chromosomal aberrations ^[8]^[9]. The inhibition of p53, coupled with the direct stimulation of mitogenic signals via calcium and inositol triphosphate second messengers, is also responsible for Cd-dependent enhanced cell proliferation. On the other hand, in specific cell systems the metal was conversely found to induce endoplasmic reticulum stress due to severe ROS and calcium signaling, which ultimately leads to apoptotic and/or autophagic cell death ^[10]^[11]^[12]^[13]. As a further DNA-directed activity, evidence has been produced that Cd may be regarded as an epigenetic modulator, given its ability to alter the global DNA methylation pattern via the down-regulation of DNA methyltransferase activity and demethylation which, upon prolonged exposure, turns into enhanced enzyme activity and genome hypermethylation. These opposite alterations may result in the up-regulation of cellular protooncogenes and the silencing of oncosuppressor genes, respectively ^[14]^[15].

Evidence collected in the literature has highlighted that the exposure of cancer cells to Cd compounds may be associated with the development of more malignant phenotypes, thereby contributing not only to the onset of cell transformation in the tumor initiation stage, which has been widely reviewed in several articles e.g., in ^[16]^[17], but also to the acceleration of tumor progression. An example of this aspect is the growth-promoting “metalloestrogen” role played by Cd on estrogen receptor α-positive breast cancer cells. On the other hand, based upon the intrinsic cytospecificity, Cd has been proven to act as a two-edged sword, conversely down-regulating viability and causing the death of a number of tumor cell lines, such as those derived from triple-negative breast cancer and hepatocarcinoma ^[18]^[19]^[20]. Cd is a transcriptional regulator that induces molecular reprogramming ^[21]; therefore, the study of differentially expressed genes has enabled the identification and classification of the molecular signatures inherent in human neoplastic cells upon Cd exposure as useful biomarkers that are potentially transferable to clinical research.

2. Molecular Signatures in Breast Cancer Cells

The search for Cd exposure-associated molecular signatures has been conducted in two cell lines, i.e., MDA-MB231 and MCF-7. The former was established from a pleural effusion of a triple-negative breast cancer (TNBC) of basal morphology, which was negative for estrogen receptor (ER) α and progesterone receptor (PR) expression and its p53 was inactivated by a mutation in codon 280 of exon 8. The ERα-positive and PR-negative MCF-7 cell line was established from a pleural effusion of a highly hormone-responsive malignant adenocarcinoma ^[22]^[23]^[24].

2.1. Molecular Signatures in MDA-MB231 Cells

Concerning TNBC cells, about a decade ago papers published by my group of researchers first contributed to this issue by investigating the effect of administering different concentrations of CdCl₂ to MDA-MB231 cells and also comparing the tumor cell behavior with that of HB2 cells, a nonneoplastic immortalized line from the human breast epithelium ^[25]. The obtained results demonstrated the cytotoxic effect of the molecule with a 50% inhibitory concentration (IC₅₀) at 96 h of 5 μM, which conversely was ineffective in modifying the survival and growth of HB2 cells ^[18]. Among the biological aspects of MDA-MB231 cells studied under this experimental condition, molecular signatures were searched that demonstrated an up- or down-regulation of the expression levels of genes coding for heat shock proteins (hsp), metallothioneins (MT), cytochrome oxidase subunits, and other factors related to apoptosis, signal transduction, and growth control, as summarized sinoptically in Table 1 (see refs. ^[18]^[26]^[27]^[28]^[29]^[30]).

Table 1. Gene expression changes in MDA-MB231 breast cancer cells exposed to 5mM CdCl₂ for 96 h.

Gene	Protein Product	Up↑ Down↓	Fold Changes
HSPA5	Endoplasmic reticulum chaperone BiP	↓	54.2
HSPA8	Heat shock cognate 71 kDa protein	↓	4.9
HSPB1	Heat shock protein β-1	↑	8.7
HSPD1	60 kDa heat shock protein, mitochondrial	↓	2
HSP90AB1	Heat shock protein HSP 90-β	↓	2.57
TRAP1	Heat shock protein 75 kDa, mitochondrial	↓	9.5
MT1A	Metallothionein-1A	↑	2.34
MT1F	Metallothionein-1F	↑	3.65
MT1G	Metallothionein-1G	↓	18.8
COX2	Cytochrome c oxidase subunit 2	↓	3
COX4	Cytochrome c oxidase subunit 4	↓	1.9
BCL2	Bcl-2	↓	53
WAF1	Cyclin-dependent kinase inhibitor 1	↑	10.4
DAPK	Death-associated protein kinase-1	↑	55
RIPK1	Receptor-interacting protein 1	↑	undetectable in control
CASP1	Caspase-1	↑	106
CASP2	Caspase-2	↑	3
CASP6	Caspase-6	↑	31.3
CASP7	Caspase-7	↑	15
CASP8	Caspase-8	↑	9.25
CASP9	Caspase-9	↑	4.7
MAPK14	Mitogen-activated protein kinase p38 α	↓	8
MAPK11	Mitogen-activated protein kinase p38 β	↓	4
MAPK12	Mitogen-activated protein kinase p38 γ	↑	7
AEG1	Astrocyte elevated gene-1 protein	↓	8.5
PLP2	Proteolipid protein 2	↑	2
FOS	Proto-oncogene c-Fos	↓	3.2
JUN	Proto-oncogene c-Jun	↓	3.5

2.2. Molecular Signatures in MCF-7 Cells

Concerning the ERα-positive MCF-7 cell line, in 2013 Lubovac-Pilav et al. ^[31] investigated the effect of chronic (up to 6 months) 10⁻⁷ M CdCl₂ exposure on the gene expression pattern by high throughput microarray technology followed by hierarchical clustering analysis and functional annotations. More recently, Liang et al. ^[32] complemented the analysis by producing data on the epigenomic as well as the transcriptomic profiles induced by short-term (72 h) 60 µM CdCl₂ treatment, further identifying also in this case the critical pathways and genes via bioinformatic studies. Their cumulative results provide a broad picture of the impact of the exposure of breast cancer cells to the metal compound at the gene signature level, with 795 differentially expressed genes identified by the authors in ^[31] and 997 differentially expressed genes identified by the authors in ^[32].

3. Molecular Signatures in Cancer Cells of the Gastrointestinal Tract

3.1. Molecular Signatures in Gastric Cancer Cells

The search for Cd exposure-associated molecular signatures has been conducted in cell lines isolated from gastric adenocarcinoma, i.e., MKN28 (well-differentiated), SNU638 (poorly differentiated with the mutated p53 gene) and AGS, the latter characterized by gene expressions typical of tumors that likely process from intestinal metaplasia ^[33]^[34]. In these cell lines Khoi et al. ^[35] examined the effects of a 4 h-treatment with 20 µM Cd on the expression levels of the PLAUR gene, coding for urokinase-plasminogen activator receptor (uPAR), demonstrating its time-dependent up-regulation. A more detailed investigation on the sole Cd-treated AGS cells brought evidence that PLAUR over-expression was to be ascribed to the activation of the ERK1/2-NFkB-AP1 pathway and that uPAR accumulation was a likely mediator of Cd-induced stimulation of cell invasiveness.

3.2. Molecular Signatures in Colon Cancer Cells

The search for Cd exposure-associated molecular signatures has been conducted in the poorly differentiated RKO cell line, which bears mutations in BRAF and PIK3CA oncogenes, and the HT-29 cell line, isolated from a primary colon adenocarcinoma ^[36]^[37].

4. Molecular Signatures in Liver Cancer Cells

The search for Cd exposure-associated molecular signatures has been conducted in HepG2 cells, isolated from a differentiated hepatocellular carcinoma.

Fabbri et al. ^[38] and Urani et al. ^[39] performed a whole-genome analysis by cDNA microarray after 24 h exposure of this cell line to 2 and 10 µM CdCl₂, considered to be low human-relevant metal concentrations. In particular, the work of Urani and coworkers has also focused on intracellular zinc displacement by Cd and its molecular consequences, as zinc is an acknowledged second messenger and transcriptional regulator. Their investigation into gene expression profiling was complemented by a miRNA expression analysis, due to the considerable involvement of their altered regulation in the carcinogenetic process. A group of eleven genes, all belonging to the metallothionein-coding family (i.e., MT1A, -B, -E, -F, -G, -H, -JP, -L, -M, -X and -2A) were found up-regulated after exposure to CdCl₂ concentrations whereas the down-regulation of 12 miRNAs and the differential-expression of 949 genes was proven in response to the treatment with the sole higher metal concentration. In particular, the down-regulation affected the genes involved in the liver function pathways (e.g., fatty acid/cholesterol metabolism and hemostasis) while the up-regulation concerned the genes involved in inflammation and cancer progression (e.g., cytokine-cytokine receptor interaction-, focal adhesion- and MAPK signaling). A subset of relevant genes was further submitted to validate their differential expression through real time-PCR.

An analysis of the KEGG database indicated that most validated genes (CAPN2, COL1A1, ITGA2, ITGA3, ITGB1, JUN and LAMB3) were associated with focal adhesions whose regulation is involved in liver cancer cell invasion and metastasis, in association with the dysregulation of the cytoskeletal component ^[40]. Interestingly, Urani and coworkers also found the up-regulation of other adherent junction pathway-related genes, i.e., SNAI1, MET, TGFBR2, RAC and CDC42, thus confirming the facilitating role of Cd in cell motility and metastatization processes. The other validated genes, i.e., FOS, HSPA6 and GADD45B, were associated to the MAP kinase pathway, which is known to play a role in hepatocarcinoma cell survival and tumor growth ^[41]. It is also of note that the two top pathways of the Cd-dependent dysregulated miRNAs were related to focal adhesions and the MAP kinase cascade.

Distinct sets of 330 and 181 genes were found impaired by the authors in ^[42] after acute and chronic low concentration-CdCl₂ treatment of HepG2 cells, respectively. The majority of them were involved in detoxification and metabolic processes in the exposure conditions in the former, and in the regulation of various signaling pathways including the inflammatory and insulin responses in the latter. A subset of relevant genes was further submitted to validate their differential expression through real time-PCR.

Under acute exposure to the metal compound, as expected for cells undergoing detoxification, the up-regulation of some members of the metallothionein gene family were found, conceivably driven, at least in part, by the down-regulation of SPINK1 as reported for colon cancer cells ^[43]. Down-regulation was also observed for ecto-5′-nucleotidase (a.k.a. CD73), the major enzyme responsible for the enzymatic dephosphorylation of the inflammation-promoting extracellular adenosine 5′-monophosphate nucleotide to the immunosuppressive adenosine. Conceivably, such down-regulation might be an indicator of a pro-inflammatory activity ^[44]. Interestingly, CYP3A7, whose product is involved in drug metabolism, was either down- or up-regulated following acute or chronic exposure, respectively, and this might be associated to the Cd cytotoxic insult in the former and the onset of a detoxification reaction by stressed cells in the latter ^[45]^[46]. Following chronic treatment, the up-regulation of the extracellular matrix protein nephronectin may complement the down-regulation of NT5E and be related to the stimulation of an inflammatory reaction, according to the evidence of protein localization in inflammatory foci in animal models of hepatitis ^[47]. Other validated differentially-expressed genes were: (i) DNAJB9, whose up-regulation may be associated with the inhibition of p53-induced senescence leading to cell mitogenic signalization and transformation; (ii) ADH4, whose lowered expression is linked to the stimulation of several cancer related pathways, including ATR, FOXM1, FOXO, MTOR, NOTCH, and the p53 downstream pathway; (iii) EGR1 coding for an anti-tumorigenic zinc-finger transcription factor; and (iv) ID1 whose down-regulation may impair the cell redox state by overproduction of ROS ^[48]^[49]^[50]^[51].

By comparison with MCF-7 breast tumor cells, 48 h-exposure to Cd also up-regulated the expression of PRMT5 and EZH2 methyltransferase genes in HepG2 cells, albeit to a lesser extent, as evidenced by the luciferase reporter assays, thereby confirming the impact of the metal on the expression of the two oncogenic epigenetic regulators also in this neoplastic cytotype ^[52].

5. Molecular Signatures in Lung Cancer Cells

The search for Cd exposure-associated molecular signatures has been conducted in the following cell lines isolated from non-small cell lung carcinoma tissues: (i) H460 characterized by mutant K-ras and wild-type p53 ^[53]^[54] and its Cd-resistant derivative RH460 established after selection via the exposure of the parental line to increasing Cd concentrations ^[55]; (ii) H1299 established from a lymph node metastasis of the lung from a patient who had received prior radiation therapy and endowed with a homozygous partial p53 deletion determining the lack of protein expression; and (iii) A549 characterized by mutant K-ras, wild-type EGFR and the properties of type II alveolar epithelial cells ^[56].

5.1. Molecular Signatures in H460 and RH460 Cells

Kim et al. ^[57] studied the induction of the multidrug resistance-associated protein 1 (MRP1), coded by the ABCC1 gene, by Cd treatment in responsive H460 vs. resistant RH460 cells. This protein is a multitasking transporter broadly involved in many aspects of cell biology and pathology spanning from cell survival and differentiation to inflammation and cancer ^[58]. The acquired Cd resistance of RH460 cells determines the absence of Cd-induced apoptosis and autophagy, occurring in the parental line, due to the lack of glycogen synthase kinase (GSK)-3β phosphorylation at serine residue and the consequent intracellular relocalization of the molecule ^[59]. Using inhibitors and siRNAs against MRP1 and GSK-3β and overexpressing GSK-3β-HA, Kim et al. ^[57] revealed the role played by the kinase in the modulation of the expression of the MRP1 molecular signature through both transcriptional regulation and direct interaction with p-Ser GSK3αβ which intervenes in MRP1 stabilization and intracellular redistribution. The obtained data represent a promising tool for the formulation of GSK-3β serine phosphorylation-inducing chemotherapeutics aimed to treat multidrug resistant lung tumors.

5.2. Molecular Signatures in H1299 Cells

It is known that various metals, including Cd, interfere with the localization, folding and function of members of the p53 protein family ^[60]. Within this context, Adámik et al. ^[61] examined whether CdCl₂ impaired the function of p63 and p73 as transcription factors. To this purpose, the different p53 family isoforms were co-transfected with p53 family-dependent luciferase reporter vectors (pGL3-MDM2-APP, pGL3-PGM1 and pGL3-BAX) into p53-deficient H1299 cells. The obtained data demonstrated that the p63 and p73 transactivation of some of the p53-dependent promoters was inhibited by exposure to 20–50 mM CdCl_2. This was also demonstrated in light of the data confirming the impairment of the binding of the factors’ core domains to p53 consensus sequences, as revealed by electrophoretic mobility shift assays. Thus, the sensitivity of p53 family proteins to Cd appears to be conserved and also active in cell-based assays and, conceivably, the resulting modulation of gene signature expression may play a central role in metal carcinogenesis.

5.3. Molecular Signatures in A549 Cells

Fujiki et al. ^[62] submitted A549 lung tumor cells to prolonged 20 mM CdCl₂ exposure and observed the onset of a high proliferative rate, EMT, stress fiber formation, cell locomotion, and resistance to antitumor drugs. From a molecular point of view, the involvement of Notch1 signalization in the Cd-promoted malignant progression was demonstrated, and which was maintained for a considerable time after the removal of CdCl₂ from the culture medium. In particular, the cell treatment was associated with the up-regulation of NOTCH1, JAG2, coding for Notch-ligand Jagged-2 protein, and MMP2, coding for matrix metalloprotease 2, an invasion-facilitating collagenase which is a prognostic factor for non-small cell lung cancer ^[63]. On the other hand, the down-regulation of NOTCH3 was a further gene signature of cell exposure to CdCl₂. The cumulative results obtained indicated that the transcriptional activity of Notch1 was stimulated by hypoxia-inducible factor 1 (HIF-1) and that the insulin-like growth factor 1 receptor (IGF-1R)/Akt/ERK/p70 S6 kinase 1 (S6K1) cascade could cooperate with Notch1 signaling and HIF-1 following the CdCl₂ treatment of A549 cells.

6. Molecular Signatures in Nasal Septum and Nasopharyngeal Cancer Cells

Since inhalation is the primary route of Cd intake, mainly by cigarette smoking and also by occupational exposure during working activities related to nickel–cadmium batteries, electroplating, and paint pigments, RPMI-2650, CNE-1 and CNE-2 cell lines were used as an in vitro model system to examine the molecular targets of Cd-induced cancer progression in nasal and nasopharyngeal epithelia.

6.1. Molecular Signatures in RPMI-2650 Cells

The RPMI-2650 line was isolated from the pleural effusion of a patient with an anaplastic squamous carcinoma of the nasal septum ^[64]. In the light of the observed Cd-dependent up-regulation of the intracellular ROS level and the down-regulation of cell proliferation, Lee et al. ^[65] compared the mRNA expression patterns of RPMI-2650 cells grown in control conditions or exposed to 0.75 µM Cd acetate for 72 h via differential display analysis. Following a preliminary analysis of gene expression, AKR1C3, coding for the aldo-keto reductase family 1 member C3 protein, was proven to undergo an increase in expression, regulated by Cd at the transcription/translation level; this up-regulation was also confirmed by Western blot analysis. This molecular signature is a hormone activity regulator and prostaglandin F synthase is responsible for monitoring the occupancy of hormone receptors and controlling cell proliferation and differentiation in a hormone-independent way ^[66]. Based on the reported Cd-induced accumulation of the Nrf2 transcription factor in the nucleoplasm and the restraining of the Cd-dependent increase in the AKR1C3 protein levels by a phosphoinositide 3-kinase (PI3K) inhibitor, it was suggested that the up-regulation of AKR1C3 may result from the augmentation of intracellular ROS, at least in part through the activation of Nrf2 and the onset of PI3K-related signalization, thereby contributing to an adaptive intracellular response to Cd cytotoxicity.

6.2. Molecular Signatures in CNE-1 and CNE-2 Cells

CNE-1 and CNE-2 cell lines were established from a well-differentiated and a poorly differentiated nasopharyngeal squamous carcinoma, respectively, a highly invasive and metastatic malignant tumor with unique ethnic and geographic distribution and prominent incidences in South China and some African areas only ^[67]^[68]. With the aim to mimic chronic low-level Cd exposure, Peng et al. ^[69] exposed both cell lines to a non-toxic CdCl₂ concentration (1 µM) for up to two weeks and observed the acquisition of more proliferative and aggressive characteristics by the cells both in vitro and in vivo. Molecular analyses revealed that chronic Cd treatment induced a remarkable up-regulation of CCND1, CCNE1, MYC and JUN, thereby demonstrating the activation of Wnt/β-catenin signaling, which is also in the parallel confirmatory data on increased β-catenin protein immunostaining in Western blots. Further studies highlighted that chronic Cd exposure induced the down-regulation of CSNK1A1, coding for the α isoform of casein kinase I, via the hypermethylation of the promoter CpG islands. On the other hand, given that this enzyme is a negative regulator of the Wnt/β-catenin pathway ^[70], this molecular event might be involved, at least in part, in the exacerbation of the malignant phenotype by neoplastic nasopharyngeal cells.

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