A review of endoplasmic reticulum (ER) stress and nanoparticle (NP) exposure

Life Sciences 186 (2017) 33–42

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Review article

A review of endoplasmic reticulum (ER) stress and nanoparticle (NP) exposure

MARK

Yi Caoa,b,⁎, Jimin Longa, Liangliang Liub, Tong Hea, Leying Jianga, Chunxue Zhaoa, Zhen Lia,b a Key Laboratory of Environment-Friendly Chemistry and Application of Ministry of Education, Lab of Biochemistry, College of Chemistry, Xiangtan University, Xiangtan 411105, PR China b Institute of Bast Fiber Crops, Chinese Academy of Agricultural Sciences, Changsha 410205, PR China

A R T I C L E I N F O

A B S T R A C T

Keywords: Nanoparticle (NP) Endoplasmic reticulum (ER) stress Nanotoxicology Nanomedicine Mechanism

Understanding the mechanism of nanoparticle (NP) induced toxicity is important for nanotoxicological and nanomedicinal studies. Endoplasmic reticulum (ER) is a crucial organelle involved in proper protein folding. High levels of misfolded proteins in the ER could lead to a condition termed as ER stress, which may ultimately influence the fate of cells and development of human diseases. In this review, we summarized studies about effects of NP exposure on ER stress. A variety of NPs, especially metal-based NPs, could induce morphological changes of ER and activate ER stress pathway both in vivo and in vitro. In addition, modulation of ER stress by chemicals has been shown to alter the toxicity of NPs. These studies in combination suggested that ER stress could be the mechanism responsible for NP induced toxicity. Meanwhile, nanomedicinal studies also used ER stress inducing NPs or NPs loaded with ER stress inducer to selectively induce ER stress mediated apoptosis in cancer cells for cancer therapy. In contrast, alleviation of ER stress by NPs has also been shown as a strategy to cure metabolic diseases. In conclusion, exposure to NPs may modulate ER stress, which could be a target for future nanotoxicological and nanomedicinal studies.

1. Introduction 1.1. An overview of nanotoxicology and nanomedicine Due to their unique properties owned by materials at the nanoscale (at least one dimension smaller than 100 nm), engineered nanoparticles (NPs) are increasingly produced and used in many commercially available products. According to the report of the Nanotechnology Consumer Product Inventory (CPI), a total of 1814 consumer products contain at least one type of NPs, including metal (Ag, Ti, Zn and Au), carbonaceous NPs (carbon black, carbon nanotubes, fullerenes, graphene), silicon-based nanomaterials (silicon and silica), and other (organics, polymers, ceramics) [1]. There are many important applications of engineered NPs in commercial products. For example, TiO2 and ZnO NPs are commonly added into cosmetic formulations as they can act as efficient filters of UV light [2]. A number of metal based NPs, particularly Ag NPs, have been developed as anti-microbial agents. Compared with conventional antibiotics, an advantage of metal based NPs is that they could effectively kill microorganisms without the occurrence of resistance [3]. Carbon nanotubes (CNTs) are increasingly produced and incorporated in many commercial products, such as rechargeable

batteries, automotive parts and sporting goods [4]. These applications of NPs in commercial products could result in exposure of human beings to NPs via dermal, inhalational and oral contact not only in workplace, but also during daily uses [1]. As such, there is a health concern about the adverse effects of NP exposure [5,6]. Besides the uses of NPs in commercially available products, another potential use of engineered NPs is in nanomedicine. For example, some types of NPs, particular CNTs and silicon-based NPs, have been shown great potential as nanocarriers for targeted drug delivery [7,8]. Some of the NPs, such as metal based NPs, possess therapeutic efficacy toward a number of cancer diseases due to their ability to selectively kill cancer cells [9,10]. NPs, for example iron oxide NPs (IONPs) and quantum dots (QDs), have been shown great potential in bio-imaging [11,12]. Despite the enthusiasm in the development of novel NPs for biomedical applications, the progress into clinical studies is relatively slow, because the adverse effects of NPs in vivo are not fully known [13,14]. Therefore, this is an urgent need to investigate the mechanisms of toxicity of NPs to ensure the safe use of them as well as to design more biocompatible NPs. To explain NP induced toxicity, different mechanisms have been proposed. It is generally agreed that oxidative stress plays an important

⁎ Corresponding author at: Key Laboratory of Environment-Friendly Chemistry and Application of Ministry of Education, Lab of Biochemistry, College of Chemistry, Xiangtan University, Xiangtan 411105, PR China. E-mail address: [email protected] (Y. Cao).

http://dx.doi.org/10.1016/j.lfs.2017.08.003 Received 23 June 2017; Received in revised form 29 July 2017; Accepted 3 August 2017 Available online 04 August 2017 0024-3205/ © 2017 Elsevier Inc. All rights reserved.

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eIF2α (α-subunit of eukaryotic translation initiation factor 2) is then phosphorylated, causing the reduction of the general rate of cellular translation [29]. However, ATF4 could escape from massive gene translation suspension, and its translation is activated by PERK- eIF2α axis. The activation of ATF4 translation in turn initiates transcriptions of apoptotic factors including C/BEP homologous protein (CHOP) and Noxa [30]. In the ATF6 pathway, ATF6 is activated after the disassociation from GRP78 and then cleaved by site-1 and site-2 proteases. The generated 50 KDa fragment (ATF6 P50) subsequently translocates to the nucleus to regulate expression of genes with ER stress response elements (ERSE) within their promoter [25]. ATF6 P50 could also regulate the expression of survival-related gene XBP-1 and/or proapoptotic transcription factor CHOP [31]. If the amount of misfolded proteins is successfully reduced, URP signaling is attenuated, leading to cell survival. However, prolonged ER stress may lead to the apoptosis of cells, which has been implicated in the development of many diseases [32].

role for NP induced toxicity. This is because a lot of NPs are chemically active that can induce reactive oxygen species (ROS) and the imbalance of oxidant and anti-oxidant systems, leading to oxidative damage [15,16]. Some of the NPs have been shown to provoke inflammatory responses and thus can disturb the function of immune systems [17,18]. Dysfunction of autophagy and lysosomes has also been suggested to play an important role [19,20]. In recent years, it has also been shown that exposure to NPs may induce endoplasmic reticulum (ER) stress as a possible mechanism for NP induced toxicity to endothelial cells [21]. In this review, we aimed at providing a comprehensive review about NP exposure and ER stress. This review may provide important information about ER stress as a mechanism for NP induced toxicity. It may also guide future studies to use NPs to modulate ER stress as a strategy for disease therapy.

1.2. An overview of ER stress The ER is the major organelle responsible for proper protein folding. Incompletely folded proteins are retained in the ER to complete the folding process with the help of molecular chaperones and folding enzymes in the lumen of ER, or are delivered to the cytosol for degradation [22]. Under normal conditions, there is an equilibrium between ER protein load and folding capacity. In contrast, genetic and environmental insults may impede the protein folding capacity and thus lead to the accumulation of misfolded proteins in ER, a condition termed as ER stress. With the accumulation of misfolded proteins in ER above a critical threshold, an adaptive signaling pathway termed as unfolded protein response (UPR) could be activated to restore ER homeostasis [22,23]. In mammalian cells, the stress signaling is generally sensed by three major ER-resident transmembrane molecules, namely IRE1 (inositol requiring protein-1), PERK (protein kinase RNA-like ER kinase) and ATF6 (activating transcription factor–6) (Fig. 1) [24]. The three stress sensors are normally inhibited in unstressed cells by the binding of ER chaperone GRP78 (78 KDa glucose-regulated protein; also known as BiP, Binding immunoglobulin protein), but activated due to the dissociation of GRP78 to bind the unfolded proteins in ER stress [22,25]. In the first pathway, the activation of IRE1 signaling could cleave XBP-1 (X-box binding protein 1) mRNA by removing an intron to generate spliced XBP-1 (XBP-1s). XBP-1s could then regulate transcriptions of ER stress proteins involved in assisting protein folding, maturation and transportation, as well as degrading misfolded proteins [26]. IRE1 may also directly activate JNK (c-Jun N-terminal Kinase) and regulate apoptosis [27,28]. When PERK is activated in ER stress,

2. ER stress as a mechanism for nanotoxicology 2.1. Morphological changes of ER by NP exposure Some studies have shown that NP could accumulate into ER and induce morphological changes of ER. For example, Zhang et al showed that exposure to Fe3O4 and PLGA-coated Fe3O4 NPs led to disrupted and dispersed ER vesicles in MCF-7 cells, whereas control cells and PLGA treated cells exhibited normal ER with flat vesicles in cytoplasm. The results suggested an activation of ER stress, although the induction of ER stress pathway was not further investigated in that study [33]. Yan et al found that CdTe QDs partially localized into ER and induced a dilation of narrow cisternae of rough ER in human umbilical vein endothelial cells (HUVECs). These changes were associated with significantly increased ER stress markers [34]. In contrast, Luo et al showed that QD750 (a QD with a covered CdSe core and ZnS shell, carboxyl polymer coated; core size 10 ± 2 nm) located within ER in 6 h in RAG cells (mouse renal adenocarcinoma cells) but did not induce ER stress in 6 h or 24 h (unaltered expression of ATF4 and CHOP). Rather, autophagy was shown to be involved in the survival against QD induced cytotoxicity in RAG cells [35]. The results from different studies by using similar NPs might indicate the role of surface coating in the induction of ER stress, or that the ER stress responses could be different in NP exposed cancer cells and normal cells. The later point will be discussed further in later section.

ER lumen p-IRE1

Xbp-1s

p-PERK

ASK-1

ATF6

p-eIFα

Apoptosis

Translation inhibition

ATF6 P50

ATF4

XBP-1 protein PDI, P58

CHOP, Noxa

Survival or death

34

Fig. 1. The three ER stress signaling pathways IRE1, PERK and ATF6. These pathways could control the fate of cells and thus involve in disease development. See more in the text.

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Fig. 2. The TEM images of liver cells of mice after repeated oral exposure to physiological saline (A), 200 mg/kg (B), or 400 mg/kg (C) of ZnO NPs. The control mice showed normal mitochondria (* in A) and ER (# in A), whereas ZnO NP treated mice showed swelling of endoplasmic reticulum (thick arrows in B and C) and ribosome degranulation (thin arrows in B and C). Reprinted with permission from Ref. [36]. Copyright Elsevier 2015.

Some recent studies also indicated that exposure to ZnO NPs could activate ER stress pathways both in vivo and in vitro, which could be associated with ZnO NP induced cytotoxicity and genotoxicity [36,44–46]. The physicochemical properties of ZnO NPs appeared to play a role in defining the ER stress response. For example, Kuang et al showed that ZnO NP induced ER stress could be size dependent, that 30 nm ZnO NPs induced a higher expression of ER stress genes compared with that of bulk and 90 nm NPs [45]. Chen et al showed that the partially soluble ZnO NPs, but not the insoluble CeO2 NPs, induced ER stress gene expression as well as CHOP and HSP proteins inside ER (Fig. 3). The authors suggested that the solubility of ZnO NPs might be important in determining ER stress activation [44]. However, it should be noticed that some insoluble NPs, such as TiO2 NPs, have also been reported to induced ER stress both in vivo and in vitro[37,47,48]. Simon et al recently showed that TiO2 scrolled nanosheets provoked a stronger ER stress response in HUVECs compared with the P25, TiO2 nanoneedles and gel-sol based isotropic NPs, which suggested a role of the morphologies rather than the solubility of NPs in ER stress activation [48]. Au NPs were shown to induce ER stress only by some recent studies. Noel et al found that Au NPs activated many ER stress markers as well as caspase 4 processing, which could ultimately lead to apoptosis of human neutrophils [49]. Grunduz et al showed that long-term exposure of HUVECs to Au NPs significantly induced XBP-1s mRNA, which was associated with NP uptake but not cytotoxicity in HUVECs. When the internalization reached a maximum, there was a gradual depletion of Au NPs which in turn led to reduced XBP-1s mRNA. This study also indicated that Au NP induced ER stress was reversible [50]. Different from the two mentioned studies, Anspach et al showed that the expression of a number of ER stress markers was not activated after exposure to a library of polymer coated Au NPs in hCMEC/D3 cells, but the inflammatory markers were induced [51]. The last study may indicate a role of surface modification with polymers to determine Au NP induced ER stress activation. Currently, some types of NPs have been shown to activate ER stress only by very limited number of studies, and more studies may be needed to confirm it. For example, Christen and Fent showed that SiO2 and Ag doped SiO2 NPs induced GRP78 and XBP-1s mRNA in human liver Huh7 cells, associated with pronounced cytotoxicity and ROS [52]. Chen et al compared ER stress activation in mice after exposure to three different MRI contrast agents, namely extremely small-sized iron oxide NPs (ESION), MnO NPs and gadopentetate dimeglumine injection (GDI). The results showed that ESION induced much lower ER stress compared with MnO NPs and GDI in various organs, which indicated that ESION could be considered as potentially safe MRI contrast agents [53]. Choi et al showed that chitosan NPs induced the mRNA of a number of ER stress markers in mouse embryos, whereas treatment with rapamycin significantly reduced chitosan NPs induced ER stress

Interestingly, NP induced morphological changes of ER were not only observed in vitro, but also in vivo. For example, Yang et al showed that repeated oral exposure to ZnO NPs induced swelling of ER and ribosome degranulation in mice livers (Fig. 2), associated with elevated expression of ER stress markers. Moreover, necrosis of liver cells and increased apoptotic protein levels were also observed, which suggested that ER stress could be the mechanism for NP induced liver injury in vivo [36]. Similarly, Yu et al also found dose-dependent ER swelling and expression of ER stress markers in TiO2 NP inhaled mice, which could be the mechanism associated with NP induced pulmonary inflammation [37]. The results from these studies are also in agreement with the theory that during ER stress, the size of the ER expands through increased biogenesis of components to increase protein folding capacity [23]. It should be noticed, however, that ER stress may also be induced after NP exposure without alterations in ER morphologies. In a recent study, Wang et al found that exposure of MDA-MB-231-TXSA cancer cells to long anodic alumina nanotubes (AANTs), but not short or medium ones, resulted in the activation of ER stress markers as decreased IRE1α and increased CHOP protein levels. TEM pictures indicated an accumulation of autophagosome, but the morphological changes in ER were not observed. The authors suggested that the cells might tolerate or recover from AANT exposure through autophagy [38]. This study suggested that the changes of ER morphologies were not necessarily correlated with NP induced ER stress. 2.2. Effects of NP exposure on ER stress pathway Some recent studies have shown the activation of ER stress after exposure to NPs, especially metal-based NPs. For example, several studies showed that exposure to Ag NPs could activate key elements in ER stress both in vivo and in vitro, which could be associated with Ag NP induced toxicity [39–43]. Interestingly, Huo et al found cell type dependent activation of ER stress pathway, that HUVECs and HepG2 cells in comparison with 16HBE cells (normal lung cells) were more resistant to ER stress activation in response to Ag NP exposure. In mice, the authors showed tissue-dependent activation of ER stress. While the lungs, livers and kidney showed significant ER stress response, the artery and tracheal tissues had lower ER stress following intratracheal instillation exposure to Ag NPs [41]. Mishra et al and Simard et al reported the activation of NLRP-3 inflammasome due to the degradation of the ER stress sensor and consequently inflammatory responses following Ag NP exposure [39,40]. Zhang et al and Christen et al found the activation of pro-apoptotic genes following ER stress induction, and down regulation of key ER stress element attenuated Ag NP induced apoptosis [42,43]. These results combined indicated that Ag NP induced ER stress could be the mechanism associated with the activation of apoptotic and inflammatory pathways. 35

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Fig. 3. The activation of ER stress by ZnO NPs but not CeO2 NPs in HUVECs. The upper panel: scatterplots of expression levels of each gene in 240 μM (A) ZnO and (B) CeO2 NPs incubated with HUVECs for 8 h versus blank control. The black line represents fold change of 1 and the pink lines indicate 2-fold change of gene expression threshold. The down panel: immunofluorescent images of ER luminal chaperone GRP78/BiP, HERP and HSP 70 proteins in HUVECs after incubating with 240 μM ZnO NPs for 8 h. Hoechst and ER tracker were used to show the nucleus and ER, respectively. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.) Reprinted with permission from Ref. [44]. Copyright American Chemical Society 2014.

decreased ATP production due to the dysfunction of mitochondria, and inhibition of ER stress by tauroursodeoxycholic acid (TUDCA) recovered ATP production in TiO2 NP exposed human lung cells [47]. Similarly, Chiu et al found that inhibition of ER stress by TUDCA decreased cytotoxicity as well as autophagy in NH2-labeled polystyrene (NH2-PS) nanosphere treated BEAS-2B cells [57]. Yan et al found that CdTe QD exposure promoted apoptosis of HUVECs associated with the activation of ER stress pathway and caspase-4, whereas chemical inhibitors of JNK, eIF2α and caspase-4 reduced QD-induced apoptosis. These results in combination suggested a role of ER stress in determining QD-induced apoptosis [34]. Our recent studies also showed that stressing macrophages or HUVECs with ER stress inducer thapsigargin (TG) enhanced the cytotoxicity of ZnO NPs particularly to lysosomes but had little to no effect on the release of inflammatory cytokines. These results combined suggested a role of ER stress in ZnO NP induced cytotoxicity [58,59]. Recently, studies have revealed a close inter-connection between ER stress and autophagy [60]. Thus, modulation of autophagy might also

activation [54]. van der Valk et al found that liposomal NP encapsulating prednisolone phosphate (LN-PLP) induced ER stress markers in aortic arches of atherosclerotic mice as well as bone marrowderived macrophages (BMDM) in vitro, thus promoted the development of atherosclerosis [55]. Dabbaghi et al recently showed that cationic polymer polyethyleneimine (PEI) dose-dependently promoted ER stress markers associated with significant cytotoxicity in Neuro2A cells [56]. The last three studies also indicated that some nanocarriers might induce ER stress associated adverse health effects, and it might be important to maintain a low level of the nanocarriers to avoid unwanted effects during drug delivery [54–56].

2.3. Modulation of ER stress and the toxicity of NPs As discussed above, activation of ER stress could be involved in NP induced toxicity; therefore it is not surprising that modulation of ER stress by chemicals may possibly alter the toxicity of NPs. For example, Yu et al showed activation of ER stress markers associated with 36

37

~ 100 nm ~ 3 nm (ESION), ~ 15 nm (MnO NPs)

60 nm, positive charged

Average size 100 nm

Average size 120 nm, negative charged

~ 250 nm; negative charged

Not characterized ~ 12 nm; citrate-capped; negative charged Size 20 nm, negative charged

30 nm, 90 nm, bulk 100–200 nm

10, 50 and 100 nm Hydrodynamic size ~ 70 nm; positive charged 20 and 70 nm; negative charged Hydrodynamic size ~ 26 nm, negative charged 15 nm; negative charged P25 (24 nm), scrolled nanosheets (L/W 178/9), nanoneedles (L/W 45/15), isotropic NPs (29 nm) Not characterized

Aspect ratio 7.8 (short), 27.7 (medium) and 63.3 (long)

~ 4 nm; negative charged

< 100 nm; negative charged

19.3 ± 5.4 nm

Hydrodynamic size ~ 250 nm; anatase:rutile, 8:2 ≤ 100 nm

15–20 nm; PLGA coated ~ 300 nm

ZnO NPs ESION, MnO NPs

NH2-PS

Chitosan NPs

Ag NPs

SiO2 and Ag doped SiO2 NPs PEI Au NPs Ag NPs

ZnO NPs

Ag NPs ZnO NPs Au NPs Fe3O4 NPs Ag NPs TiO2 NPs

AANTs

CdTe QDs

ZnO NPs

TiO2 NPs

TiO2 NPs Ag NPs

Fe3O4 NPs

MCF-7 cells

16HBE14o-lung cells Human Chang liver cells

Mice

Mice

LDLr−/− mice (in vivo), BMDM (in vivo) MDA-MB-231-TXSA and RAW264.7 cells HUVECs

HepG2 cells MRC5 cells human neutrophils RAW 264.7 cells THP-1 cells HUVECs

Neuro2A cells HUVECs 16HBE cells (in vitro); mice (in vivo) Mice

Mouse morula-stage embryos ZFL cells (in vitro); zebrafish (in vivo) Huh7 cells

RAW 264.7, BEAS-2B cells

HUVEC Mice

Models

100 μg/mL for 24 h.

Inhaled to 2.5, 5.0 and 10.0 mg/m3 NPs for 28 d. 50 and 100 μg/mL for 24 and 48 h 4 μg/mL for 3–24 h

Gavaged for 90 d (200, 400 mg/kg)

10 μg/mL for 24 h.

10 mg/kg, twice/week for 2 or 6 weeks (in vivo); 10 or 40 μg/mL for 24 h 100 μg/mL AANTs for 3 d.

1 μg/mL for 24 h 25 and 50 μg/mL for 16 h 100 μg/mL for 3 h 6.25–50 μg/mL for 24 h 1–25 μg/mL for 1 or 24 h 2 μg/cm2 for 1–24 h

3–25 μg/mL for 24 h 8 μg/mL from 2 to 35 d 2 μg/cm2 from 4 to 24 h (in vitro); 0.1–0.5 μg/g (in vivo) 100 mg/kg/d for 3 d

0.05–0.5 mg/mL for 6–24 h (in vitro); 0.1–5 mg/mL for 24 h (in vivo) 0.05–0.5 mg/mL for 4 and 24 h

100 μg/mL for 24–28 h

Increased GRP78, IRE-1α, p-IRE-1α and CHOP protein Increased ER tracker staining and protein levels of p-PERK, p-IRE1, peIF2α, XBP-1s, ATF6, GRP78 and CHOP. Disrupted and dispersed ER.

Increased GRP78, ATF4 and CHOP mRNA. Increased XBP-1s mRNA Increased XBP-1s, CHOP, GRP78, p-IRE1α, p-PERK, p-eIF2α protein or mRNA. Increased PERK, eIF2a, ATF4, CHOP, JNK, GRP94 mRNA in livers (30 nm > 90 nm > bulk) Increased CHOP protein Increased CHOP and ERN1 mRNA Increased p-PERK, p-IRE and ATF6 proteins. Increased CHOP mRNA, p-IRE1α, IRE1α, CHOP proteins. Increased p-PERK protein and ATF6 degradation. Increased CHOP, ERdj4, HERPUD1 mRNA (scrolled nanosheets > others). Increased CHOP mRNA in aortic arches (in vivo); PERK and CHOP mRNA in BMDM Increased ER-tracker staining and CHOP protein, decreased IRE1α protein (long AANT only). Dilated ER; increased protein levels of GRP78, GRP95, p-PERK, peIF2α, ATF4, CHOP, p-JNK. Swelling of ER; increased GRP94, GRP78, XBP-1 and PDI-3 mRNA, CHOP and p-JNK protein (livers) Swelling of ER; increased GRP78, CHOP and p-IRE1α protein (lungs)

Increased GRP78 and XBP-1s mRNA.

Increased GRP78, ATF6 and XBP-1s protein or mRNA.

Increased XBP-1s, CHOP, p-PERK, p-eIF2α, HSP proteins or mRNA Increased GRP78, HSP, CHOP, XBP-1s mRNA or protein in various organs (MnO NPs > ESION) Misfolded protein aggregates; increased ER-tracker staining and IRE1α protein. Increased PERK, IRE-1α, ATF4, CHOP, GRP78 protein or mRNA.

240 μM 4–24 h 2, 5, 10 μg/g for 1 d 5–40 μg/mL, up to 16 h.

ER stress induction

Exposure

[33]

[47] [43]

[37]

[36]

[34]

[38]

[55]

[39] [46] [49] [61] [40] [48]

[45]

[56] [50] [41]

[52]

[42]

[54]

[57]

[44] [53]

References

Abbreviations: AANT: anodic alumina nanotube; ATF: activating transcription factor; BMDM: bone marrow-derived macrophages; CHOP: C/EBP homologous protein; eIF2α: α-subunit of eukaryotic translation initiation factor 2; ER: endoplasmic reticulum; ESIOP: extremely small-sized iron oxide NP; GRP: glucose-regulated protein; HERPUD1: homocysteine inducible ER protein with ubiquitin like domain 1; HSP: heat shock proteins; HUVEC: human umbilical vein endothelial cell; IRE1α: inositol-requiring protein-1α; JNK: c-JUN NH2-terminal kinase; LN-PLP: liposomal nanoparticles loaded with prednisolone; NH2-PS: NH2-labeled polystyrene; NP: nanoparticle; PDI-3: protein disulfide isomerase-3; PEI: polymer polyethyleneimine; PLGA: acid terminated, lactide/glycolide; PERK: protein kinase RNA-like kinase; QD: quantum dot; XBP-1: X-box binding protein 1.

LN-PLP

Physicochemical properties

NPs

Table 1 The induction of ER stress by NP exposure.

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Fig. 4. PEG-PE micelles induced different ER stress pathway in A549 cancer cells compared with MRC-5 and 293T normal cells. A. Different protein profiles associated with ER stress after micelle treatment. GADD34 was only activated in micelle treated MRC-5 and 293T normal cells but not A549 cancer cells. B. Scheme of the relationship between PEG-PE-induced molecular events in cancer cells and normal Cells. Reprinted with permission from Ref. [70]. Copyright American Chemical Society 2012.

3. Modulation of ER stress by NP in nanomedicine

alter ER stress mediated toxicity after NP exposure. Park et al showed activation of ER stress pathway in Fe3O4 NP treated RAW264.7 cells. Meanwhile, activation of autophagy was also observed, showing as increased autophagy related proteins and accumulation of autolysosomes containing damaged ER. Blockage of the fusion between autophagosomes and lysosomes by bafilomycin A1 increased NP induced apoptosis. The authors suggested that Fe3O4 NPs induced autophagy preceding apoptosis through ER stress in RAW264.7 cells [61]. To summarize from this section, a number of studies showed that exposure to NPs might alter the morphology of ER and activate ER stress markers (summarized in Table 1). Meanwhile, it has also been shown that the activation of ER stress pathway was commonly associated with the activation of apoptotic pathway, and modulation of ER stress by chemicals has been shown to alter NP induced toxicity, which suggested a role of ER stress in Nanotoxicology. To the best of our knowledge, only two studies showed that Ag NP induced ER stress was associated with inflammatory responses due to the activation of NLRP-3 inflammasome [39,40]. Therefore, the relationship between NP induced ER stress and inflammation may still need further studies.

It is generally agreed that ER stress plays an important role in human pathology, such as the development of metabolic diseases and cancer, and ER has been considered as a potential target to treat ER stress related diseases [23,62]. As such, modulation of ER stress by using engineered NPs is also a possible way to cure certain diseases. In the next section we will discuss how this strategy is realized for disease therapy.

3.1. Selective activation of ER stress by NPs for cancer therapy Cancer cells are particularly sensitive to ER stress mediated apoptosis [63]. Therefore, selective activation of ER stress by NP exposure could be a possible way for cancer treatment. This strategy has been tested by several studies. For example, it has been shown that Ag NPs, Au NPs and [Gd@C82(OH)22]n could selectively promote an unmanageable ER stress in cancer cells, which ultimately led to apoptosis [64–66]. Yasui et al found that pretreatment with PEGylated nanogel containing gold NPs (GNG) enhanced the sensitivity of cancer cells to Xirradiation due to enhanced apoptosis and impaired DNA repair capacity via ER stress activation [67]. This study highlighted the possibility 38

39

Not characterized

Average size 5.48 nm

L 736 nm ± 460 nm, inner D and outer D 33.0 ± 8.0 and 90.0 ± 10.0 nm.

[Gd@C82(OH)22]n

Realgar QDs

AANTs (loaded with TG)

HFF, THP-1 and MDA-MB 231-TXSA cells

JEC cells

MCF-7 and ECV304 cells

SCCVII and A549 cells H9C2 cells A549, MRC-5, 293T cells

K562 cells

Suppressed GRP78, PDI, and HSP mRNA Increased IRE-1α and CHOP proteins. Increased p-PERK, p-eIF2α, p-IRE1α, CHOP and ATF4 proteins, misfolded proteins in ER Increased ER stress associated proteins (proteomic assay) Increased IRE-1α, GRP78, p-PERK proteins. Reduced PDI and GRP78 proteins. ER dilation, Increased IRE-1α, PERK, eIF2α, ATF4, ATF6, XBP-1s, CHOP proteins in cancer cells Reduced protein processing in ER and increased CHOP mRNA (DNA microarray). Dilation of ER; increased GRP78 and CHOP mRNA and proteins. Increased IRE1α and GRP78 proteins and ER tracker staining

Decreased CHOP, ERdj4 and XBP-1s mRNA.

Suppressed GRP78 and CHOP proteins.

Accumulation in ER; increased CHOP, GRP78 and pJNK proteins Suppressed GRP78 and CHOP proteins.

Effects on ER stress

Anti-cancer

Anti-cancer

Anti-cancer

Anti-cancer Anti-cardiomyopathy Anti-cancer

Anti-cancer

Anti-cardiomyopathy Anti-cancer Anti-cancer

Prevention of myocardial injury Anti-age-related macular degeneration Metabolic diseases treatment

Anti-cancer

Applications

[72]

[68]

[64]

[67] [75] [70]

[65]

[74] [69] [66]

[77]

[78]

[76]

[71]

References

Abbreviations: AANT: anodic alumina nanotube; CHOP: C/EBP homologous protein; D: diameter; eIF2α: α-subunit of eukaryotic translation initiation factor 2; ER: endoplasmic reticulum; ERdj4: ER-localized DnaJ 4; GNG: PEGylated nanogel containing gold nanoparticles; GRP: glucose-regulated protein; HSP: heat shock proteins; IRE1α: inositol-requiring preotein-1α; JNK: c-JUN NH2-terminal kinase; L: length; MCP-1: monocyte chemoattractant protein-1; NP: nanoparticle; PDI: protein disulfide isomerase; PEG-PE: Poly(ethylene glycol)-phosphoethanolamine; PLGA: poly (DL-lactide-co-glycolide); QD: quantum dot; TG: thapsigargin; XBP-1s: X-box binding protein 1 spliced.

Not characterized Not characterized Not characterized

Average size 7 nm 20 nm, citrate coated 2 nm and 10 nm; negative charged

GNG CeO2 NPs PEG-PE micelles

Average size 214.8 nm, negative charged

PLGA NPs containing γoryzanol CeO2 NPs Au NPs Ag NPs

1–3 nm, 5–6 nm, 15–20 nm

MCP-1 transgenic mice AsPc1 cells MCF-7 and T-47D cells

Size between 50 and 100 nm

ZnS NPs

Au NPs

Mice retinal pigment epithelial cells Obese ob/ob mice

Average size 50 nm, negative charged

H460, H157, H1650, and NL20 cells H9C2 cells

Average size 98.9 ± 2.64 nm

PLGA NPs containing LY294002 Curcumin NPs

Models

Physicochemical properties

NPs

Table 2 Modulation of ER stress by NPs for disease therapy.

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possible nano-formulation for the treatment of age-related macular degeneration, the leading cause for irreversible visual impairment. In mice retinal pigment epithelial cells, the authors showed that ZnS NPs were capable of inhibiting ROS generation and proteins of GRP78 and CHOP induced by H2O2 or TG treatment, thus protected cells from apoptosis. The authors suggested that ZnS NPs may help maintaining normal homeostasis through the regulation ER stress [78]. To summarize from this part, some studies have shown that certain types of NPs were capable of attenuating ER stress, which could be used for metabolic disease therapy (summarized in Table 2). Typically, these NPs could also inhibit oxidative stress, which suggested that the antioxidant properties might be crucial for the NPs to attenuate ER stress. In contrast, NPs that may induce oxidative stress have been extensively shown to induce ER stress as discussed earlier.

of GNG as sublethal radiosensitizer for cancer therapy. In a different study, Wang et al synthesized novel realgar QDs to improve water solubility of realgar. The authors showed that the QDs were capable of inducing activation of ER stress pathway and dilation of ER, which ultimately led to apoptosis and necrosis of JEC cancer cells [68]. Saha et al showed Au NPs activated IRE-1α and CHOP, which altered cellular secretome, interrogated bidirectional crosstalk between the pancreatic cancer cells and the pancreatic stellate cells, and ultimately inhibited tumor growth [69]. These studies in combination indicated that NPs could be used to selectively activate ER stress pathway in cancer cells. Wang et al further analyzed why cancer cells could be more sensitive to NP induced ER stress. By using PEG-PE micelles, the authors found that NP induced ER stress was associated with apoptosis activation and lipid synthesis in cancer cells, whereas in normal cells the ER stress feedback protein GADD34 inhibited proapoptotic ER stress signaling and protected normal cells from NP induced apoptosis (Fig 4) [70]. NPs could also be used as carriers for ER stress inducing agents to selectively kill cancer cells. For example, Hou et al loaded PLGA NPs with LY294002, a potent inhibitor of phosphatidylinositol 3-kinase (PI3K) with anti-tumor activity both in vivo and in vitro. A large portion of NPs containing LY294002 localized in ER and consequently provoked pronounced ER stress in cancer cells, which could be responsible for the anti-cancer effects [71]. In a recent study, Wang et al delivered ER stress inducer TG by AANTs, and showed that the novel AANT based formulations effectively induced apoptosis of cancer cells due to the activation of ER stress. Moreover, AANTs themselves were non-cytotoxic to cancer cells, which suggested the excellent biocompatibility [72]. To summarize from this part, some of the NPs were capable of selectively inducing ER stress and consequently apoptosis of cancer cells. Biocompatible nanocarriers have also been used to deliver ER stress inducing agents to induce apoptosis of cancer cells (summarized in Table 2). These studies combined indicated that NPs could be used to target ER in cancer cells as a strategy for cancer therapy.

4. Conclusion ER stress has been implicated in human pathologies. In this review, we reviewed studies about ER stress and NP exposure. Exposure to NPs has been shown to induce ER stress, showing as alterations of ER morphologies and activation of ER stress pathways both in vivo and in vitro. Furthermore, modulation of ER stress by chemicals has been shown to alter NP induced toxicity, which confirmed ER stress as the mechanism for NP induced toxicity. Meanwhile, exposure of cancer cells to ER stress inducing NPs or NPs containing ER stress inducer could lead to ER stress mediated apoptosis, whereas alleviation of ER stress by NPs with anti-oxidant properties has been shown as a strategy to cure metabolic diseases. Thus, modulation of ER stress by NPs could be a potential way for disease therapy. Combined, ER stress could be altered after NP exposure, which should be considered for future nanotoxicological and nanomedicinal studies. Acknowledgement This work was financially supported by The Scientific Research Fund of Hunan Provincial Education Department (16C1551), Xiangtan University grant (15XZX19) and Xiangtan University start-up grant (15QDZ47).

3.2. Alleviation of ER stress by NPs for metabolic disease therapy Convincing data indicated that a number of human diseases, particularly metabolic diseases, are associated with prolonged ER stress [23,73]. As such, it is not surprising that alleviation of ER is a potential strategy for the treatment of metabolic diseases. To date, some studies have attempted using NPs with anti-oxidant properties to cure metabolic diseases. A pilot study by Niu et al showed that CeO2 NPs suppressed expression of key ER stress associated genes and exhibited cardioprotective effects (inhibition of vascular dysfunction, anti-inflammation and anti-oxidative stress) in transgenic mice of cardiomyopathy [74]. A later study by Younce et al also showed that CeO2 NPs attenuated high glucose induced ROS, expression of ER stress genes and apoptosis of cardiomyoblasts [75]. Recently, Li et al synthesized curcumin NPs, and found that the NPs protected cardiomyocytes from palmitate induced apoptosis through the inhibition of ER stress activation and NADPH oxidase mediated oxidative stress [76]. These studies combined indicated the possible cardioprotective ability of NPs with anti-oxidant properties through the inhibition of ER stress. Recently, Kozuka et al encapsulated γ-oryzanol into PLGA NPs to improve the bioavailability of γ-oryzanol. PLGA NPs containing γ-oryzanol markedly ameliorated fuel metabolism, improved function of hypothalamus and pancreatic islets, and dramatically decreased inflammatory responses in obese mice. ER stress in liver and adipose tissues were significantly decreased after NP treatment, which could be the mechanism associated with metabolically beneficial effects [77]. This study suggested the possibility of NPs as carriers to deliver bioactive substance with low bioavailability. It also suggested the potential of using NPs to alleviate ER stress as a strategy to cure metabolic diseases. In a different study, Karthikeyan et al synthesized ZnS NPs as a

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