J Cancer Res Clin Oncol DOI 10.1007/s00432-015-1916-3

REVIEW – CANCER RESEARCH

The functional role of peroxiredoxin 3 in reactive oxygen species, apoptosis, and chemoresistance of cancer cells Lianqin Li · Ai‑Qun Yu 

Received: 12 August 2014 / Accepted: 12 January 2015 © Springer-Verlag Berlin Heidelberg 2015

Abstract  Purpose  The mammalian peroxiredoxin (PRX) family contains six members that provide antioxidant defense in different cell types by removing reactive oxygen species (ROS) through conserved active cysteines. Different from other members, PRX3 is predominantly located in mitochondria, a major apoptosis mediator. The purpose of this review is to summarize the findings on PRX3 concerning its role in ROS removal, apoptosis, and chemoresistance of cancer cells. Methods  The relevant literature from PubMed and Medline databases is reviewed in this article (1994-2014). Results  Because of fast growth and relatively low supply of oxygen in cancer cells, ROS production from mitochondria is exaggerated to an extent that overwhelms cellular antioxidant defenses resulting in oxidative stress. As an active responder to oxidative stress, PRX3 is accordingly up-regulated in cancer cells to remove cellular ROS and inhibit apoptosis, which provides a favorable microenvironment for cell proliferation. Lianqin Li and Ai-Qun Yu have contributed equally to this work. L. Li (*)  Department of Obstetrics and Gynecology, Yantai Affiliated Hospital of Binzhou Medical University, 717 Jinbu Street, Muping‑district, Yantai 264100, China e-mail: [email protected] A.‑Q. Yu  Institute of Psychology, Chinese Academy of Sciences, Beijing 100101, China A.‑Q. Yu  Graduate School of Chinese Academy of Sciences, Beijing 100049, China A.‑Q. Yu  Canvard College, Beijing Technology and Business University, Beijing 101118, China

Conclusion  Since most of chemotherapy or radiotherapy for cancers is through ROS increase and apoptotic induction, PRX3 might be involved in the chemotherapeutic resistance of cancers. Keywords  Peroxiredoxin (PRX) · Reactive oxygen species (ROS) · Oxidative stress · Apoptosis · Cancer

Introduction Since the definition of “peroxiredoxin family” by Chae et al. in 1994 (Chae et al. 1994), the function of peroxiredoxin (PRX) genes and related mechanisms have been studied extensively and intensively. The mammalian PRX family contains six members which are, respectively, named PRX1, PRX2, PRX3, PRX4, PRX5, and PRX6. Although they are originally identified from different species, tissues, or cells/cell lines, the products of PRX genes have conserved reactive cysteine residue(s) in the active site(s) by which hydrogen peroxide (H2O2) is reduced (Chae et al. 1999). Working as scavengers of reactive oxygen species (ROS), PRXs influence diverse cellular processes including growth, differentiation, apoptosis, and carcinogenesis. In recent years, the involvement of PRX genes in carcinogenesis has become a hot issue for researchers. Accumulating evidence has proven that PRXs play an important role in cancer development, progression, and recurrence. As the third member of PRX family, PRX3 is predominantly located in mitochondria (Watabe et al. 1997; Chae et al. 1999). According to the report by Liu et al., PRX3 was synthesized in cytoplasm and was transported to mitochondria by a sphingosine kinase-1-binding protein RPK118 (Liu et al. 2005). By scavenging mitochondrial ROS, PRX3 is essential to maintain normal mitochondrial function (Araki

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et al. 1999; Wonsey et al. 2002). Since mitochondrion is a main ROS source and a major apoptosis mediator, the present review is focused on the regulatory role of PRX3 in ROS level and apoptosis of cancerous cells.

Removal of ROS by PRX3 The gene PRX3 was isolated from murine erythroleukemia cells in 1989 and was tentatively named MER5 (Yamamoto et al. 1989). The gene product was once called antioxidant protein 1 (AOP1) when it was found to have antioxidant activity (Tsuji et al. 1995). PRX3 protein possesses two typical cysteines that are oxidized by H2O2. The oxidized cysteines are then reduced by mitochondrial thioredoxin 2 (TRX2) or glutaredoxin 2 (Grx2) (Chae et al. 1999; Hanschmann et al. 2010). PRX3, TRX2, and TRX reductase 2 (TrxR2) constitute the first line in the protection against oxidative stress of mitochondria (Miranda-Vizuete et al. 2000; Rabilloud et al. 2001; Drechsel and Patel 2010). On the other hand, the active cysteine residue of PRX3 is hyperoxidized to reversible sulfinic acid or irreversible sulfonic acid. The former can be reversed by sulfiredoxin (SRX) in the presence of ATP (Chang et al. 2004b; Woo et al. 2005). Cytosolic SRX was translocated to mitochondria under oxidative stress, which provided an essential support for PRX3 recovery (Noh et al. 2009; Bae et al. 2009, 2012). In addition, it was reported that cytosolic human T cell cyclophilin A (CyP-A) bound to PRX3 and supported the peroxidase activity of PRX3 (Jäschke et al. 1998; Lee et al. 2001), although the physiological significance remained to be unknown. Just as a human being communicates with other people, a gene has all kinds of connections with other genes, and PRX3 is no exclusion when its product executes antioxidant function. According to the reports by Wonsey et al. and Guo et al., PRX3 is regulated by its upstream gene c-Myc (Wonsey et al. 2002; Guo et al. 2000). Nevertheless, PRX3 expression was decreased only by 50 % in the absence of c-Myc, which suggested the presence of unidentified genes as other regulators of PRX3 (Wonsey et al. 2002). Afterward, Chiribau et al. reported that FOXO3A, a forkhead box transcription factor, mediated PRX3 expression resulting in the resistance to oxidative stress in human cardiac fibroblasts (Chiribau et al. 2008), and Jeong et al. confirmed that the expression of PRX3 was partially dependent on FOXO3A in pheochromocytoma cells (Jeong et al. 2011). Another study conducted by Cunniff et al. reported the coexistence of cytoplasmic FOXM1 and mitochondrial PRX3 in mesothelioma cells (Cunniff et al. 2013). One more candidate regulator for PRX3 might be p53. p53 showed anti-apoptotic properties by increasing PRX3 expression and decreasing intracellular ROS in vascular smooth muscle cells (Popowich et al. 2010), which

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was in accordance with previous report that low levels of p53 were sufficient for up-regulation of several genes with antioxidant products (Sablina et al. 2005). Further investigation is needed to determine the precise links between p53 and PRX3 in cancer cells. In addition, microRNAs (miRNAs), a class of small non-protein-coding molecules, have also been reported to control cell growth and cancer progression by negatively regulating PRX3 expression (He et al. 2012; Li et al. 2013a). As a nuclear transcription factor, c-Myc-encoded protein transduces intracellular signals to the nucleus, resulting in the regulation of cell proliferation, differentiation, apoptosis, and malignant transformation. c-Myc is one of the most frequently deregulated oncogenes in human cancers when it serves as a crucial regulator in multiple cellular events. According to the reports by Zhang et al. and Jensen et al., c-Myc was negatively regulated by hypoxia-inducible factor 1 (HIF-1) (Zhang et al. 2007; Jensen et al. 2011). Since hypoxia is a common feature of cancer cells, HIF-1 is overexpressed as a kind of hypoxic adaptation (Zhong et al. 1999; Talks et al. 2000), and down-regulation of c-Myc contributed to cancer cell survival under hypoxic conditions (Okuyama et al. 2010). One more interacting gene with c-Myc was PRX1 as identified by yeast two-hybrid screen (Mu et al. 2002). PRX1 biologically reduces the transcription ability of c-Myc and suppresses its transforming activity, while both of PRX1 and c-Myc proteins exert anti-apoptotic effects in response to oxidative stress (Mu et al. 2002). The expression of PRX1 was elevated in human lung cancer cells treated with hypoxia/reoxygenation, and the up-regulation was dependent on nuclear factor (erythroid-derived 2)-related factor 2 (Nrf2) that was activated in response to the hypoxic and unstable oxygenation microenvironment in various cancers (Kim et al. 2007). Furthermore, Kim et al. demonstrated Nrf2-dependent over-expression of PRX3 in human lung cancer (Kim et al. 2011), and quercetin up-regulated the expression of PRX3 through the activation of Nrf2/Nrf1 transcription pathway in trabecular meshwork cells (Miyamoto et al. 2011). However, things were far from being concluded since c-Myc was reported to be activated by hypoxia, resulting in up-regulation of HIF-1 in cancer cells (Doe et al. 2012; Chen et al. 2013). More importantly, the cross talks between HIF-1 and p53 (Fels and Koumenis 2005; Obacz et al. 2013), HIF-1 and FOXM1 (Xia et al. 2009), or even FOXO3a and c-Myc (Ferber et al. 2012) added weights to the complex associations among these genes. It might be the complex associations among these genes that caused divergent expression patterns of PRX3 in different cancer types or in the different areas of the same sample, depending on the redox status or/and the contexts of cancer cells. We presented a network by which PRX3 communicates with other genes to protect against oxidative stress in cancer cells (Fig. 1).

J Cancer Res Clin Oncol

Fig. 1  Illustration of PRX3 network. Under oxidative stress of cancerous cells, PRX3 is up-regulated by p53, Nrf2, FOXO3A, and FOXM1. PRX3 is also controlled positively by its upstream gene c-Myc through Nrf2-PRX1 pathway. On the other hand, the expression of PRX3 is inhibited by HIF-1 as a response to hypoxic microenvironment of cancers. miRNAs miR-23b and 383 are involved in cell growth and cancer progression by negatively regulating PRX3.

In addition, interaction of mitochondrial PRX3 with LZK enhances LZK-induced NF-kB activation through IkB kinase (IKK) complex, resulting in apoptotic inhibition. Oxidized PRX3 can be reduced by mitochondrial TRX2 and Grx2, respectively, and recovered by cytosolic SRX that is translocated to mitochondria. The activity of PRX3 might also be stimulated or supported by cytosolic CyP-A that binds to PRX3

The expression of PRX3 and its involvement in apoptosis of cancerous cells

up-regulated in nearly all the cancers except MM, in which the PRX3 positivity (36 % of all detected cases) was less than that of PRX1 (69 %), PRX2 (75 %), PRX5 (67 %), and PRX6 (83 %) (Kinnula et al. 2002). In addition to the association of PRX3 expression with cell growth in breast and cervical cancers, respectively (Chua et al. 2010; Hu et al. 2013), the pattern of PRX3 immunostaining showed correlations with clinicopathological variables of some cancers. For example, the immunohistochemical expression of PRX3 was positively associated with tumor stage and prostate-specific antigen level in prostate cancer (Basu et al. 2011). PRX3 over-expression was correlated with poor cell differentiation of breast cancer, hepatocellular carcinoma, and cervical cancer (Karihtala et al. 2003; Qiao et al. 2012; Hu et al. 2013). These observations make PRX3 a promising candidate for cell proliferation marker and a potential prognostic biomarker for cancers. By a review of substantial literature, we can draw the conclusion that the up-regulation of PRX3 in diverse cancers is involved in tumor progression or chemotherapeutic resistance through controlling ROS level and inhibiting ROS-induced apoptosis of the cancer cells (Whitaker et al. 2013; Wang et al. 2013, 2014). Mitochondrion-specific PRX3 has been suggested to regulate cytochrome c release from mitochondria, which is a critical early step in the

Because of active and indefinite growth of cancer cells, excessive ROS is produced in the cells, especially in mitochondria (Li et al. 2013b; Tehan et al. 2013). As an active responder to oxidative stress, PRX3 (or together with PRX5, another mitochondrial PRX gene) was significantly up-regulated in most common malignancies including breast cancer (Noh et al. 2001; Karihtala et al. 2003; Chua et al. 2010), hepatocellular carcinoma (Choi et al. 2002; Qiao et al. 2012), malignant mesothelioma (MM) (Kinnula et al. 2002), lung cancer (Kim et al. 2011; Park et al. 2006), cervical cancer (Kim et al. 2009; Hu et al. 2013), colorectal neoplasm (Wu et al. 2010), prostate cancer (Basu et al. 2011; Whitaker et al. 2013), and endometrial cancer (Han et al. 2012). Mitochondrial ROS can easily diffuse to the cytosol through both inner and outer mitochondrial membranes (Sena and Chandel 2012), which induced the response of cytosolic PRXs to oxidative stress in cancers. Simultaneous over-expression of PRX3 and other PRX genes (Table 1) indicates that PRXs work synergistically to protect cancer cells against oxidative stress (Shen and Nathan 2002; McDonald et al. 2014). Notably, PRX3 was prominently

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Table 1  Expression futures of PRX genes in diverse cancers

Cancers of

PRX1

PRX2

PRX3

PRX4

PRX5

PRX6

Source

Breast

↑ – ND ND ND ↑ ↑ ↑ – ND ↑ – ND

↑ – ND ND ND ↑ – – ↑ ND ↑ – ND

ND ↑ ND ND ND – – – – ND – ↑ ND

ND ↑ ND ND ND ↑ – – – ND ↑ – ND

ND – ND ND ND ↑ – – – ND ↑ – ND

Noh et al. (2001) Karihtala et al. (2003) Chua et al. (2010) Choi et al. (2002) Qiao et al. (2012) Kinnula et al. (2002) Kim et al. (2011) Park et al. (2006) Kim et al. (2009) Hu et al. (2013) Wu et al. (2010) Basu et al. (2011) Whitaker et al. (2013)





↑ ↑ ↑ ↑ ↑ – ↑ ↑ ↑ ↑ ↑ ↑ ↑







Han et al. (2012)

Liver Mesothelium Lung Cervix Colon Prostate ND no data, ↑ up-regulation, – no change

Endometrium



Table 2  PRX3-mediated apoptosis of cancer cells/cell lines treated with various chemicals Cancer cells/cell lines

Cervical cancer Thymoma T lymphoma Neuroblastoma APL Breast cancer Mesothelioma Ovarian cancer

Chemicals

Action on PRX3

Staurosporine ABRA Imexon Isothiocyanate Or auranofin MPP+ ATO PP2 Nitroxides TS

PRX3-siRNA Inactivation PRX3-transfection Oxidation Oxidation PRX3-siRNA Down-regulation Down-regulation Down-regulation Inactivation

Cisplatin

PRX3-siRNA

Impact on cellular activities

Source

ROS

Growth

Apoptosis

↑ ↑ ↓ ND ND ND ↑ ND ↑ ↑

ND ND ↓ ND ND ND ND ND ↓ ND

↑ ↑ ↓ ↑ ↑ ↑ ↑ ↑ ND ND

(Chang et al. 2004a) Shih et al. (2001) Nonn et al. (2003) Brown et al. (2008) (Cox et al. 2008a) De Simoni et al. 2008 Vivas-Mejía et al. (2009) Liu et al. (2010) Cunniff et al. (2013) Newick et al. (2012)





Duan et al. (2013)

ND

ND no data, ABRA abrin A-chain, APL acute promyelocytic leukemia, ATO arsenic trioxide, MPP+ 1-methyl-4-phenylpyridinium, PP2 4-amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazolo [3,4-d] pyrimidine, ↑ increase, ↓ decrease

apoptosis signaling pathway (Wonsey et al. 2002; Chang et al. 2004a). According to the previous studies, PRX3 oxidation is an early event in chemical-induced apoptosis of cancer cells (Cox et al. 2008b; Brown et al. 2008). As summarized in Table 2, there have been numerous reports indicating an active response of PRX3 to various proapoptotic stimuli (including anticancer chemicals) and the participation of PRX3 in cancer cell apoptosis. Chang et al. demonstrated that depletion of PRX3 by RNA interference in HeLa cells resulted in increased intracellular levels of H2O2 and sensitized the cells to apoptotic induction by staurosporine (Chang et al. 2004a). Abrin, a kind of type II ribosome-inactivating protein, contains a toxophoric A-chain (ABRA) with protein synthesis inhibitory activity and a lectin B-chain binding to D-galactose moieties of the cell membrane (Lin et al. 1970). Shih and colleagues

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identified PRX3 product as an ABRA-interacting protein by a yeast two-hybrid system (Shih et al. 2001). The interaction attenuated the antioxidant activity of PRX3, resulting in the increase in intracellular ROS level and the activation of apoptotic signaling in HeLa cells (Shih et al. 2001). On the contrary, over-expression of PRX3 in thymoma cells displayed decreased levels of cellular H2O2 and protected the cells against apoptosis caused by anticancer drug imexon (Nonn et al. 2003). Auranofin, a gold(I)-containing antirheumatic compound, was proven to be an inhibitor of TrxR and was suggested to be a potential agent in cancer chemotherapy (Marzano et al. 2007; Madeira et al. 2012). In T lymphoma cells treated with isothiocyanate or auranofin, PRX3 was selectively oxidized, followed by disruption of mitochondrial redox homeostasis and subsequent apoptosis of cancer cells (Brown et al. 2008; Cox et al. 2008a). Silencing

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of the PRX3 expression in human neuroblastoma cells sensitized the cells to oxidative damages and apoptosis induced by 1-methyl-4-phenylpyridinium (MPP+) (De Simoni et al. 2008). According to the report by Vivas-Mejía et al., the expression of PRX3 was down-regulated and the apoptosis was enhanced in the acute promyelocytic leukemia (APL)derived cells treated with arsenic trioxide (ATO) (VivasMejía et al. 2009). The similar mechanism was found, respectively, in breast cancer cells treated with 4-amino5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2) (Liu et al. 2010) and in mesothelioma cells treated with nitroxides (Cunniff et al. 2013). Thiostrepton (TS) is a thiazole antibiotic that has been shown to has modest antitumor activity in a mouse model (Halasi et al. 2010). One of the underlying mechanism for the activity might be that TS disabled the TR2/TRX2/PRX3 mitochondrial antioxidant pathway by covalently adducting cysteine residues in PRX3 as evidenced in MM cells (Newick et al. 2012). In ovarian cancer cells, siRNA targeting of PRX3 expression enhanced cisplatin-induced apoptosis (Duan et al. 2013). In summary, the anticancer drugs or potential anticancer chemicals induced apoptosis of cancer cells by increasing ROS level and oxidizing PRX3, inactivating PRX3 antioxidant activity, or down-regulating PRX3 expression, which suggested that PRX3 might be potentially targeted for chemotherapeutic effects. PRX3 regulates apoptosis through interaction with other gene products in addition to direct mitochondrial pathway. For example, PRX3 was recruited to the complex of leucine zipper-bearing kinase (LZK) and IkappaB kinase (IKK) through binding to LZK, which protected the IKK complex from oxidative inactivation and enhanced the LZK-induced NF-kappaB activation (Masaki et al. 2003). Activation of NF-kappaB in fibroblasts antagonized apoptosis by downregulating the c-Jun amino-terminal kinase cascade (De Smaele et al. 2001), while inhibition of constitutive NFkappaB in the mantle cell lymphoma cell lines led to cell cycle arrest in G(1) and rapid induction of apoptosis (Pham et al. 2003). Further investigation demonstrated that the apoptosis was associated with the down-regulation of bcl-2 family members bcl-x(L) and bfl/A1, the activation of caspase 3, and the release of cytochrome c from mitochondria (Pham et al. 2003).

Conclusion and perspectives PRX family is a group of antioxidant proteins which are responsive to divergent stimuli that promote ROS production. By reducing intracellular ROS level through reactive cysteine sites, PRXs are involved in various cell processes including proliferation, differentiation, apoptosis, aging, and carcinogenesis. Each member of PRX family seems to

play its particular role by working in different places or in different conditions. Mitochondrion-specific PRX3 plays an active role in responding to oxidative stress in most common cancers. By scavenging extra ROS, PRX3 protects cancer cells against apoptosis and provides a favorable microenvironment for cell proliferation. Since most of chemotherapy for cancers is through increase in ROS level and apoptotic induction of cancer cells (Srinivas et al. 2004; Alexandre et al. 2006; Singh et al. 2007; Brown et al. 2010), some researchers have suggested PRX3 to be a potential target for cancer therapy on the basis of above fact (Zhang et al. 2009; Song et al. 2011). Although the overlapping peroxidatic activities of PRXs contributed to drug resistance of cancer cells (Kalinina et al. 2012), PRX3 played an indispensable role in apoptotic regulation (Chua et al. 2010; Li et al. 2013b; Whitaker et al. 2013; Wang et al. 2014; McDonald et al. 2014). Therefore, we have reason to look forward to the desired effects by suppressing the expression of PRX3. Conflict of interest  The authors declare that there is no conflict of interest.

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The functional role of peroxiredoxin 3 in reactive oxygen species, apoptosis, and chemoresistance of cancer cells.

The mammalian peroxiredoxin (PRX) family contains six members that provide antioxidant defense in different cell types by removing reactive oxygen spe...
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