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Golla, U. Regulation of Signaling Pathways by Selenium in Cancer. Encyclopedia. Available online: https://encyclopedia.pub/entry/49407 (accessed on 04 August 2024).
Golla U. Regulation of Signaling Pathways by Selenium in Cancer. Encyclopedia. Available at: https://encyclopedia.pub/entry/49407. Accessed August 04, 2024.
Golla, Upendarrao. "Regulation of Signaling Pathways by Selenium in Cancer" Encyclopedia, https://encyclopedia.pub/entry/49407 (accessed August 04, 2024).
Golla, U. (2023, September 20). Regulation of Signaling Pathways by Selenium in Cancer. In Encyclopedia. https://encyclopedia.pub/entry/49407
Golla, Upendarrao. "Regulation of Signaling Pathways by Selenium in Cancer." Encyclopedia. Web. 20 September, 2023.
Regulation of Signaling Pathways by Selenium in Cancer
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This entry is adapted from the peer-reviewed paper 10.3390/ijms23147972

Selenium is an essential, naturally occurring trace mineral element, implicated in a diverse set of biological processes that impact health and disease. Supplementing chemotherapy and radiotherapy with selenium has been shown to have benefits against various cancers. This approach has also been shown to alleviate the side effects associated with standard cancer therapies and improve the quality of life in patients.

selenium selenoprotein cancer chemoprevention chemotherapeutic

1. Introduction

Due to the high incidence rate of individuals diagnosed with cancers and the corresponding harmful effects to their quality of life from treatment, determined efforts have focused on improving cancer prevention and treatment, which have been pursued throughout the literature [1][2][3][4]. Cancer is a disease characterized by normal cells mutating and proliferating uncontrollably and/or by the improper gene expression or signaling pathways of specific targets, which results in malignant transformations [5][6]. Typically, chemotherapy, immunotherapy, radiation therapy, or surgery is employed to treat cancer patients [3][7]. The earlier the cancer is detected, staged, and aggressively treated, the better the prognosis of the disease, and this may also prevent cancer from metastasizing to other parts of the body [7]. Blood cancers, such as acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), are characterized by the over-proliferation of blasts in the blood, bone marrow, and other tissues, which can hinder the hematopoietic pathways. AML is a rapidly progressive cancer that is heterogenous in nature, making it difficult to effectively treat; therefore, it is associated with low survival and high relapse rates. This is especially true for the elderly, who commonly exhibit pre-existing conditions that can be compounded by side effects from the treatment or the disease itself [8]. Among the cancers that children are diagnosed with, leukemia is one of the most prevalent, wherein acute lymphoblastic leukemia (ALL) is responsible for about one fourth of all childhood malignancies [9].
Selenium is an essential, naturally occurring trace mineral element, implicated in a diverse set of biological processes that impact health and disease [10][11][12][13][14][15][16]. Among the three elements (oxygen, sulfur, and selenium) from the chalcogen group of the periodic table that are incorporated into biological macromolecules, both sulfur and Se exhibit similar chemical characteristics in terms of valence states (−2, 0, +2, +4, and +6). Although the two elements are utilized in a variety of biochemical reactions, selenium is found to be more abundant in biological systems than sulfur due to its stability, reactivity, and the greater polarity of its chemical bonding [17][18][19]. Selenium is a key component in several metabolic pathways, including the antioxidant system, DNA stability and the production of proteins and nucleic acids, redox signaling, thyroid hormone metabolism, and the immune system [13][14]. The amino acid selenocysteine (Sec) is present in the active site of 25 selenoproteins in humans (e.g., glutathione peroxidase (GPX) or thioredoxin reductase (TXNRD), Figure 1) and selenoproteins require selenium to function properly [10][20]. The selenium-based enzymes such as GPX and TXNRD (Figure 1) have important roles in multiple biological pathways and are utilized by cells to protect against oxidative damage on the cell membrane and in DNA, which may prevent or protect against cancer [21][22]. Although the majority of studies have highlighted the chemopreventive role of selenium, recent randomized control trials and observational studies have reported that selenium alone failed to exhibit anticancer activity [23][24][25]. Conversely, selenium supplementation has raised several concerns for increased risks of cancer and detrimental effects, especially in conjunction with type 2 diabetes [26]. The oxidation of NADPH to NADP+ by enzymes such as thioredoxin reductases (Figure 1) is necessary for the reduction of reactive oxygens species (ROS) such as hydrogen peroxide (H2O2) to water by glutathione peroxidases. These GPXs significantly contribute to protecting cells against oxidative damage from ROS and reactive nitrogen species (RNS) including superoxide, H2O2, and nitric oxide (NO) [20][27]. Selenium supplementation modulates the NO-mediated apoptosis induced by cadmium [28]. A deficiency in selenium results in the increased expression of inducible nitric oxide synthase (iNOS) and NO production [29]. The crystal structures of the selenoproteins in Figure 1 were obtained from the Protein Data Bank (PDB) and generated in PyMOL [30]. The significant role of selenium in major biological processes and activities suggests the potential therapeutic benefit that may come from incorporating it into standard-of-care cancer therapies.
Figure 1. Selenium is required to ensure the expression and functionality of selenoproteins to protect cells from oxidative damage. (A) Structure of selenoenzyme glutathione peroxidase GPX1 in Bos taurus (Bovine), which plays an essential role in detoxifying hydrogen peroxide (PDB: 1GP1). Selenium is a crucial intracellular part of this enzyme’s ability to protect cells. (B) Crystal structure of recombinant rat thioredoxin reductase TXNRD1 with oxidized C-terminal tail depicting the selenocysteine residue that is key for its catalytic activity (PDB: 3EAO). The functionally important selenocysteine residue present in the active site of (A,B) is highlighted in color. (C) Scavenging of ROS by GPX1 and catalytic redox cycle of selenoprotein thioredoxin (Trx) by Trx reductase TXNRD1. GR, glutathione reductase; GSH, glutathione (reduced form); GSSG, glutathione disulfide.

2. Regulation of Signaling Pathways by Selenium in Cancer

2.1. Selenoproteins Play a Role in Cancer

Selenium is present in all mammals and is utilized by selenoproteins (Figure 1), a family of proteins that need the selenium containing amino acid, selenocysteine, to effectively carry out target processes [31][32]. Selenium has its own mRNA codon that allows for its insertion as selenocysteine into selenoproteins [33]. Selenoproteins play a crucial role in protecting cells from cancer. Thus, a deficit of selenium in the diet could result in the depletion of selenoprotein levels and consequently deprive the body of their benefits [33][34]. Selenoproteins also have roles in DNA-repair and cytokine control pathways [35][36]. Differential expression profiles of GPXs and TXNRDs indicate that selenoprotein families have importance in carcinogenesis, the occurrence of cancer, and influence the immune-cell subtypes, mechanistic cell infiltration, and tumor cell stemness [33][34]. These genes were found to have key roles in cancer survival (e.g., TXNRD1 and TXNRD3 are correlated with a poor prognosis), the tumor microenvironment (e.g., TXNRD1, GPX1, and GPX2 are linked to tumor mutagenesis and development), and drug sensitivity (TXNRD1, GPX1, GPX2, and GPX3 are associated with the formation of drug resistance) [21]. A low expression of GPX3 has been correlated with the poor prognosis (overall survival and disease-free survival) of AML patients and suggests that targeting substrates related to the glutathione metabolic pathway may advance AML treatment [37]. The antioxidant thioredoxin system has also been reported to be upregulated in cancer cells and linked to cancer development, relapse, and chemoresistance in acute leukemia [38][39]. The ROS-facilitated signaling of c-Jun activation domain-binding protein-1 and thioredoxin have been correlated with the pathology, poor survival, and relapse in AML-M5 patients [40]. Recent findings indicate that single nucleotide polymorphisms (SNPs) in selenoprotein and selenium metabolic pathway genes alone or in combination with suboptimal levels of selenium contribute to cancer development [41]. Research and development considering the link between selenoproteins and tumorigenesis may allow for the design of more effective targeted therapies [21][38].

2.2. Role of Selenoproteins in Hematological Malignancies

Selenoproteins play an important biological role in maintaining human health by regulating selenium transport, redox homeostasis, thyroid hormone metabolism, and immunity, as stated above. The dysregulation of selenoproteins and selenium deficiency can result in several serious disorders such as cancer, cardiovascular disease (Keshan disease), osteoarthritis, liver disease (hepatopathy), arthropathy (Kashin–Beck disease), and a defective immunity against viral infections [20][42][43]. The dysregulation of the cellular redox systems plays an important role in both acute and chronic hematological malignancies [44]. The ubiquitous loss of mitochondrial thioredoxin reductase (TrxR2) in mice was associated with embryonic death at embryonic day 13 and the presentation of smaller embryos that were severely anemic with increased apoptosis in the liver [45]. A pan-cancer expression analysis revealed the association of selenoprotein P (SELENOP) with a better prognosis in most cancers, but a poorer prognosis in brain glioma and uterine corpus endometrioid carcinoma [46]. Furthermore, the overexpression of Glutathione peroxidases (GPXs) in AML patients compared to normal controls was significantly associated with a poor prognosis of overall survival [47]. The overexpression of the selenoprotein Glutathione peroxidase 4 (GPX4) contributed to the poor prognosis of aggressive diffuse large B-cell (DLBC) lymphoma via the inhibition of ROS-induced cell death [48]. Further, the downstream regulator of GPX4, i.e., SECISBP2 (Selenocysteine Insertion Sequence-Binding Protein 2), which regulates various selenoproteins, was revealed as a novel prognostic predictor of DLBC lymphomas and may serve as a potential therapeutic target [49]. Recently, Eagle K et al. integrated pan-cancer genetic dependency data with that of a comprehensive enhancer landscape and identified SEPHS2, a selenoprotein biosynthesis gene, as a highly AML-selective dependency encoded by a Myb-regulated oncogenic enhancer. The suppression of the SEPHS2-regulated production of selenoproteins by diet selectively renders AML susceptible to oxidative stress without affecting normal hematopoiesis [50]. Overall, the current literature highlights the potential role of selenoproteins and selenium metabolism in different cancers including hematopoietic malignancies.

2.3. Inorganic and Organic Selenium Compounds Exert Therapeutic Activities

Multiple reports have shown that selenium in varying forms (e.g., organic, inorganic, or as selenoproteins) can exert anticarcinogenic or antimutagenic properties that allow them to serve as promising candidates for anticancer therapies (Figure 2 and Figure 3) [11][27][51]. It has been reported that Se possesses anti-proliferative, anti-inflammatory, and anti-viral activities in addition to immune altering properties and has been implicated in various cancers [51][52]. Inorganic selenium-based compounds (such as selenite and selenate) tend to metabolize into hydrogen selenide and organic forms of selenium (such as diselenides, selenides, selenoesters, methylseleninic acid (MSA), 1,2-benzisoselenazole-3[2H]-one and selenophene-based derivatives, and selenoamino acids and Selol) metabolize into methylselenol [52][53]. These highly reactive, redox-active metabolites (e.g., hydrogen selenide or methylselenol) exhibit distinct cellular functions and toxicities that give rise to their chemopreventive or chemotherapeutic properties [52][53][54].
Figure 2. Chemical structures of sodium selenite (SS), methylselenocysteine (MSC), and seleno-L-methionine (SLM), which are well studied selenocompounds that have demonstrated anti-cancer properties.
Figure 3. Selenium-based compounds exhibit chemopreventive or chemotherapeutic properties through regulation of various processes such as cell cycle arrest, apoptosis, angiogenesis, etc.
Previous reports have focused on investigating the properties imparted by the organic selenocompounds such as methylselenocysteine (MSC) and seleno-L-methionine (SLM) (Figure 2) [52][55]. These studies have shown that, at supra-nutritional concentrations, MSC and SLM exhibit anti-angiogenic and anti-cancer effects. The well-studied inorganic selenium compound selenite (Figure 2) is clinically utilized and supplemented in the diet of patients with the endemic Keshan disease [56][57]. Keshan disease arises due to insufficient dietary selenium levels, which can result in cardiovascular atrophy if not properly addressed [56][57]. The supplementation of selenite into the diet successfully treats Keshan disease and the associated symptoms, suggesting the therapeutic benefits that can be imparted by selenite [56][57].
Several studies indicate the ability of selenocompounds to work well with conventional cancer therapies (e.g., chemotherapy or radiotherapy) to improve their efficacy toward malignant cells and decrease their associated off-target or adverse effects [58]. Multiple human studies [59][60][61] have demonstrated a decrease in the toxicity of the standard-of-care chemotherapies (e.g., cisplatin, doxorubicin, cyclophosphamide, and busulfan), and noted that the therapeutic benefit was not adversely affected upon supplementing cancer therapy with selenium either in the form of sodium selenite (SS) or the organic SLM (Figure 2). Xenograft studies have shown that SLM was more efficacious in improving conventional chemotherapies relative to SS [62][63]. The ability of organic Se-methylselenocysteine (MSC) versus SS and SLM (Figure 2) to efficiently produce methylselenol, a metabolite that has been suggested to regulate a large part of the interactions with standard chemotherapies, suggests that MSC is more promising and beneficial than SS and SLM [64][65]. Notably, the anticancer activity of MSC and SLM partly depends on the endogenous expression levels of various enzymes such as kynurenine aminotransferases (KATs) and cystathionine γ-lyase (γ-cystathionase) in target tissues along with their ability to synthesize chemopreventive metabolites, either methylselenol and/or seleno-keto acid metabolites, in situ [66]. SS is still preferentially studied by some labs because of its demonstrated increased selectivity for exerting a ROS-influenced cytotoxic effect that reduces the cell proliferation in malignant cells when compared to normal cells [67][68]. However, the greater genotoxicity induced by inorganic SS relative to SLM or MSC could result in possible late toxicities (e.g., myelodysplasia or acute leukemia), an important factor when selecting an agent to work beneficially with DNA-damaging cancer treatments [69].

2.4. Selenium-Based Compounds or Proteins Act by Various Modes of Action

Reports have indicated that selenium-based compounds or selenoproteins exhibit chemotherapeutic activity by regulating various biochemical pathways related to apoptosis [1], cell proliferation [51][70], cell cycle arrest [71][72], necrosis, autophagy, ferroptosis, necroptosis, entosis, anoikis, NETosis, or mitotic catastrophe imparting cytotoxic effects or cell death (Figure 3) [33][73]. The selenocompounds with promising anticancer activity were summarized in Table 1. The selenoprotein glutathione peroxidase 4 (GPX4) and glutathione can regulate ferroptosis to protect the cell from oxidative damage (e.g., excessive ROS/RNS production) [74][75]. However, the overexpression of GPX4 has been correlated with the poor prognosis and overall survival of diffuse large B-cell lymphoma [49]. Advantageous responses from selenium-related cancer treatments have also been shown to be imparted by protein modification, the impairment of tumor angiogenesis, and the regulation of processes associated with DNA repair/damage, metastasis, or the endoplasmic reticulum (ER) and oxidative stress responses (Table 1; Figure 3). Selenium has been linked to metastasis in various cancers and is thought to impart anti-metastatic properties (Figure 3), such as reducing the expression of Osteopontin and suppressing cell motility, migration, invasion, and angiogenesis [73][76]. Selenocompounds have also been reported to increase the activity of macrophages and enhance cell respiration [77].
Table 1. List of selenium-based compounds with promising anticancer activity.

S. No.

Compound

Redox Property

Cytotoxicity Mechanism

References

1

Selenate

Proapoptotic, genotoxic

Activates protein phosphatase 2A, which inhibits various signaling cascades such as phosphatidylinositol 3-kinase (PI3K)/Akt pathway.

Induces apoptosis, but at a relatively high concentration.

[78]

2

Selenite/Sodium selenite (SS)

Proapoptotic, prooxidative, genotoxic, inhibits cell proliferation

Activation of extracellular signal-regulated protein kinase (ERK) pathway.

Inhibition of autophagy through PI3K/Akt pathway

[79][80]

3

Selenocysteine (SeCys)

Antioxidant

Induces apoptosis through the cell cycle arrest, and oxidative damage.

Paraptotic-like effect mediated by ER stress.

[81][82]

4

Selenomethionine (SeMet)

Proapoptotic, proliferation inhibition

Pro-apoptotic effects in several cancer cell lines.

Activation of p53-dependent proteins.

Non-toxic and non-genotoxic.

[1][83]

5

Methylselenocysteine (MSC)

Proapoptotic, anti-angiogenic, proliferation inhibition

Anti-cancer effects in various cell lines, including promyelocytic leukemia.

ER stress and mitochondrial dysfunction/signaling

[84][85]

6

Methylselenic acid (MSA)

Pro-apoptotic, anti-inflammatory, pro-oxidant, anti-angiogenic

Induces cytotoxicity through DNA damage.

Regulation of PI3k/Akt, ERK1/2, and p38 pathways

[72][86]

7

Selenodiglutathione (SDG)

Antioxidant, pro-apoptotic

Induction of apoptosis through ROS and oxidative damage.

[87]

8

Methylselenol

Pro-apoptotic; inhibits cell growth

Inhibition of the ERK1/2 pathway activation and c-Myc expression.

Induces cell cycle arrest.

[88]

9

Ebselen

Anti-inflammatory, antioxidant, protects against oxidative stress as well as DNA damage

As an antioxidant, Ebselen induces apoptosis through many pathways.

Induces ROS generation and oxidative damage

[89]

10

Ethaselen

Proliferation suppression, synergistically effective with cisplatin against resistant leukemic cells

Induces ROS and apoptosis by TrxR inhibition

[90][91]

11

Dimethyl diselenide

Antioxidant

Induces NADPH quinone oxidoreductase

[92]

12

Zidovudine derivatives

Pro-apoptotic

Induced apoptosis through the mitochondrial pathway

[93]

13

Phenylindolyl Ketone Derivative

Pro-apoptotic

Induced apoptosis through cell cycle arrest and inhibition of tubulin polymerization.

[94]

14

Combretastatin 4-A analog

Inhibit tubulin polymerization

Inhibition of cell growth.

[95]

15

Diphenyl diselenide

Antioxidant, inhibitor of nociception

Protective against genotoxic substances.

Induces apoptosis through oxidative damage.

[96][97]

16

Selol

Cytotoxic effects, inhibits proliferation, apoptotic

Induced apoptosis in resistant cancer cell lines including leukemia through oxidative damage.

[98]
The amount of the selenium agent administered can influence whether prooxidant or antioxidant activity is observed. Typically, nutritional doses exert antioxidant and chemopreventive effects relative to supranutritional concentrations that can induce prooxidant and anticancer pathways [99]. The metabolites derived from selenium have been linked to the triggering of oxidative stress in cells via the production of ROS/RNS, which in turn leads to the oxidation of protein thiol moieties [27][51]. Selenium-based compounds have been shown to exhibit chemopreventive and anticancer properties through prooxidant activities and the regulation of cellular redox homeostasis by altering thiol groups in multiple metabolic pathways, stimulating the production of ROS/RNS, and regulating changes in the chromatin [52][84].
Selenium-based compounds have been shown to modulate cellular responses by regulating p53 phosphorylation [71][83][100][101]. Selenium treatments have been demonstrated to increase the host cell’s reactivation of a UV-damaged reporter plasmid template [102], indicating its possible role in DNA repair [101][103]. However, it has been established that selenium can only regulate DNA repair in wildtype p53 containing cells [101][103]. The selenoprotein thioredoxin reductase and redox factor 1 (Ref-1) are needed for p53 cysteine reduction, which allows for the prevention of DNA damage [103][104][105]. Studies have shown that SLM activates DNA repair and shields cells from DNA damage without inducing cell cycle arrest or apoptosis [71][83][100][101][103]. In one study, mouse embryonic fibroblasts, either wildtype or null for p53 genes, were pre-treated with the nontoxic agent, SLM [101]. This pretreatment induced a DNA repair response and protected the fibroblasts against DNA damage in the presence of UV radiation or UV-mimetic chemotherapy [101]. The beneficial activity imparted by SLM was not seen in cell lines that were null for the tumor suppressor p53 gene. Therefore, p53 may be crucial for distinguishing healthy and cancer cells [101]. On a similar note, selenium nanoparticles exhibited an inhibitory effect on p53’s ability to mitigate chemotherapy-induced diarrhea and possibly serve as potential chemoprotectants [106].
The addition of Se alongside treatment with DNA-damaging chemotherapeutics has been shown to selectively protect healthy tissues and prevent the typically observed dose-limiting toxicity [101]. This has allowed for the administration of increased chemotherapeutic doses and has induced a cytotoxic effect on cancer cells [101]. Human tumor xenograft murine models (human squamous cell carcinoma of the head and neck, FaDu and A253, and colon carcinomas HCT-8 and HT-29) that were administered seleno-L-methionine prior to and during chemotherapy treatment experienced an improved tolerance to higher doses of irinotecan [107]. The ability to treat tumor-bearing mice with higher concentrations of drugs allowed for an enhanced efficacy towards chemoresistant tumors [107]. Phase 1 trials have explored the potential of SLM to improve chemotherapy and found that patients could tolerate high doses of SLM without displaying adverse toxic effects [108][109].
Selenium-derived compounds have been shown to alter the expression of various target genes or modulate the interplay between signaling networks [84][110]. Powers and co-workers demonstrated that selenium supplementation in the form of selenite plays a role in cellular signaling and its consequences by regulating the highly conserved Delta–Notch signaling pathway [56]. In vitro studies indicated that selenite treatment on primary mouse hepatocytes, MCF7 breast adenocarcinoma cells, or HEPF2 liver carcinoma cells altered the transcription levels of various genes involved in the Delta–Notch signaling network (e.g., Notch1) [56]. The intraperitoneal administration of selenite (2.5 mg/kg) to mice resulted in significantly reduced Notch1 expression levels in liver and kidney tissues [56]. These results provide support for selenite’s role as an inhibitor in the Notch signaling pathway and its promise as a targeted therapy of Notch, which has been correlated with the prognosis in various cancers, fibrosis, and neurodegenerative diseases [56][111].

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