Endoplasmic Reticulum Protein 29 Research Articles

Euchromatic histone lysine methyltransferase 2 facilitates radioresistance in prostate cancer by repressing endoplasmic reticulum protein 29 transcription.

Prostate cancer is one of the most common cancers in men. This study was conducted to investigate the role of euchromatic histone lysine methyltransferase 2 (EHMT2) and endoplasmic reticulum protein 29 (ERP29) in the progression of radioresistance in prostate cancer. The expression of EHMT2 and ERP29 in prostate cancer cells and during the progression of radioresistance was detected using quantitative reverse transcription-polymerase chain reaction and western blotting, and the interaction between EHMT2 and ERP29 was investigated. The proliferation of transfected cells under x-ray irradiation was determined using the methyl thiazolyl tetrazolium and colony formation assays. Flow cytometry was used to analyze the apoptosis of the transfected cells under x-ray irradiation. Nude mice were subcutaneously injected with prostate cancer (DU145) cells stably transfected with sh-ERP29 or sh-NC. The effect of ERP29 expression on radioresistance in nude mice was assessed by x-ray irradiation. The expression of EHMT2 was upregulated and that of ERP29 was downregulated in prostate cancer cells during radioresistance progression. EHMT2 downregulation suppressed radioresistance in DU145 and androgen-sensitive prostate cancer (LNCaP) cells. In irradiated DU145 cells, EHMT2 inhibition decreased the number of colonies and accelerated apoptosis. The transcription of ERP29 was suppressed by EHMT2 by upregulating H3K9me2 and downregulating H3K4me3, thereby regulating radioresistance in prostate cancer cells. In addition, the downregulation of ERP29 promoted the progression of radioresistance in prostate cancer cells in nude mice. EHMT2 promotes radioresistance in prostate cancer cells by repressing ERP29 transcription.

ERp29 forms a feedback regulation loop with microRNA-135a-5p and promotes progression of colorectal cancer

Expression of endoplasmic reticulum (ER) stress-associated genes is often dysregulated in cancer progression. ER protein 29 (ERp29) is abnormally expressed in many neoplasms and plays an important role in tumorigenesis. Here, we showed ERp29 is a novel target for microRNA-135a-5p (miR-135a-5p) to inhibit the progression of colorectal cancer (CRC); correspondingly, ERp29 acts as an oncoprotein in CRC by promoting proliferation and metastasis of CRC cells, and suppressing apoptosis of the cells. More importantly, we found that miR-135a-5p expression is reversely upregulated by ERp29 through suppressing IL-1β-elicited methylation of miR-135a-5p promoter region, a process for enterocyte to maintain a balance between miR-135a-5p and ERp29 but dysregulated in CRC. Our study reveals a novel feedback regulation loop between miR-135a-5p and ERp29 that is critical for maintaining appropriate level of each of them, but partially imbalanced in CRC, resulting in abnormal expression of miR-135a-5p and ERp29, which further accelerates CRC progression. We provide supporting evidence for ERp29 and miR-135a-5p as potential biomarkers for diagnosis and treatment of CRC.

Interleukin 10 Plays an Important Role in Neonatal Rats with Hypoxic-Ischemia Associated with B-Cell Lymphoma 2 and Endoplasmic Reticulum Protein 29.

Interleukin 10 (IL-10) is a synthetic inhibitor of human cytokines with immunomodulatory and anti-inflammatory effects. This study was designed to investigate the expression variation of IL-10 in the multiple sites including cortex, hippocampus, and lung tissues of neonatal hypoxic-ischemic (HI) rats and explore the crucial role of IL-10 in alleviating HI brain damage. In this study, neonatal Sprague-Dawley rats were subjected to the right common carotid artery ligation, followed by 2 h of hypoxia. The expression of IL-10 in the cortex, hippocampus, and lung tissues was measured with immunohistochemistry, real-time quantitative polymerase chain reaction (RT-qPCR), and western blot (WB). Immunofluorescence double staining was performed to observe the localization of IL-10 in neurons and astrocytes. Moreover, not-targeting and targeting IL-10 siRNA lentivirus vectors were injected into the rats of the negative control (NC) and IL-10 group, respectively, and the mRNA levels of B-cell lymphoma 2 (Bcl-2) and endoplasmic reticulum protein 29 (ERp29) were detected by RT-qPCR following IL-10 silence. The results demonstrated that the IL-10 expression was markedly increased after HI and IL-10 were colocalized with neurons and astrocytes which were badly injured by HI insult. In addition, Bcl-2 and ERp29 were remarkably decreased following IL-10 mRNA interference compared with the NC group. Our findings revealed that IL-10 exerted its antiapoptotic and neuroprotective effects by regulating the expression of Bcl-2 and ERp29, indicating that IL-10 may be a promising molecule target for HIE treatment.

Dimerization of ER-resident molecular chaperones mediated by ERp29

The lectin chaperones calnexin (CNX) and calreticulin (CRT) localized in the endoplasmic reticulum play important roles in glycoprotein quality control. Although the interaction between these lectin chaperones and ERp57 is well known, it has been recently reported that endoplasmic reticulum protein 29 (ERp29), a member of PDI family, interacts with CNX and CRT. The biochemical function of ERp29 is unclear because it exhibits no ERp57-like redox activity. In this study, we addressed the possibility that ER chaperones CNX and CRT are connected via ERp29, based on our observation that ERp29 exists as a dimer. As a result, we showed that CNX dimerizes through ERp29. These results endorse the hypothesis that ERp29 serves as a bridge that links two molecules of CNX. Also, we showed that similar complexes such as CNX–CRT were formed via ERp29.

ERp29 affects the migratory and invasive ability of human extravillous trophoblast HTR‐8/SVneo cells via modulating the epithelial‐mesenchymal transition

Dysfunction of trophoblast metastasis into the endometrium is the main cause of pre-eclampsia (PE); however, the factors affecting this process are still unclear. In this study, we found that endoplasmic reticulum protein 29 (ERp29), one molecular chaperone of the endoplasmic reticulum, was aberrantly upregulated in the placenta of pre-eclamptic patients compared with healthy controls. Then, an in vitro study using human extravillous trophoblast HTR-8/SVneo cells showed that ERp29 upregulation could inhibit the migratory and invasive ability of HTR-8/SVneo cells, while ERp29 downregulation had the opposite effect. Mechanical experiments confirmed that ERp29 blocked trophoblast metastasis via inhibiting the process of epithelial-mesenchymal transition and affecting the Wnt/β-catenin signaling pathway. In conclusion, this study revealed the important role of ERp29 in trophoblast metastasis and improved the mechanical understanding of PE occurrence.

ERp29 inhibition attenuates TCA toxicity via affecting p38/p53- dependent pathway in human trophoblast HTR-8/SVeno cells

Intrahepatic cholestasis of pregnancy (ICP) is a liver disorder occurred in pregnant women, and the mechanism for such disease is still unclear. The bioinformatics analysis of our previous study has revealed the abnormal expression of endoplasmic reticulum protein 29 (ERp29) in placental tissue of ICP patients. In this study, the function of ERp29 was further explored using in vitro model of ICP. The results showed that up-regulation of ERp29 occurred in TCA (taurocholic acid)-treated human trophoblast HTR-8/SVeno cells, and ERp29 inhibition reversed TCA toxicity via attenuating G2/M arrest and cell apoptosis. Mechanical study revealed ERp29 inhibition suppressed phosphorylation and kinase activity of p38, thus subsequently affecting expression and phosphorylation of p53 (ser18) as well as the transcriptional activity of p53. The conduction of this study might confirm the important role of ERp29 in ICP and which would be helpful for the development of target therapeutic method for ICP.

MiR-205-5p downregulation decreases gemcitabine sensitivity of breast cancer cells via ERp29 upregulation.

Breast cancer is the most common cancer in women worldwide, and the incidence and mortality rates are increasing every year. Dysregulation of microRNAs (miRNAs or miRs) is an important step in the initiation and development of breast cancer. Previous studies demonstrated that miR-205-5p is closely associated with occurrence and development of breast cancer; however, underlying mechanisms remain unclear. In the present study, reverse transcription-quantitative polymerase chain reaction assays were used to analyze miR-195-5p and endoplasmic reticulum protein 29 (ERp29) levels in breast cancer and matched normal tissues. Western blot analysis was performed to analyze ERp29 and heat shock protein 27 (HSP27) protein expression levels. Cell viability, flow cytometry and luciferase reporter assay were used to examine cell proliferation, apoptosis and direct miRNA-mRNA binding, respectively. The results revealed that miR-205-5p expression in breast cancer tissues and cell lines was decreased compared with normal tissues and a normal cell line. Overexpression of miR-205-5p significantly augmented cytotoxicity effects of gemcitabine treatment in MDA-MB-231 and BT549 cells. It was observed that miR-205-5p negatively regulated ERp29 expression in breast cancer cells. Dual luciferase assays confirmed that ERp29 was a target of miR-205-5p in breast cancer cells. Additionally, following the established gemcitabine-resistant MDA-MB-231 cells (MDA-MB-231/GEM), ERp29 and HSP27 expression was upregulated and miR-205-5p was downregulated compared with parental cells. Overexpression of miR-205-5p reversed gemcitabine resistance in MDA-MB-231/GEM cells. In conclusion, the present study indicated that miR-205-5p may inhibit gemcitabine resistance in breast cancer cells via inhibition of ERp29 expression.

Endoplasmic reticulum protein 29 (ERp29) as a novel prognostic marker and tumor suppressor in osteosarcoma

BackgroundDiverse aberrancy in genetic background, protein profiling, and biological pathways have emerged as important factors hindering discovery of effective treatment of osteosarcoma. In a previous study, we used a proteomic approach to identify some osteosarcoma-related proteins by analysis of protein profiling in individual patients through primary cell culture. Endoplasmic reticulum protein 29 (ERp29) emerged as a protein of interest for further study since accumulating evidence suggests it has broad functions in tumorigenesis of different types of cancer. Importantly, until now no report on examination of the expression patterns of ERp29 in osteosarcoma has been published. MethodsIn this study, an expression of ERp29 was examined in patient-derived osteosarcoma cells (7 cases) and normal bone graft-derived osteoblasts (7 cases) using western blotting. Expression profile of ERp29 in 94 osteosarcoma cases was investigated using immunohistochemically stained on formalin-fixed paraffin-embedded biopsied tissue. An association with clinicopathologic parameters and the patient survival was evaluated. The doubling time of five osteosarcoma cells lines expressing different levels of ERp29 was determined by a cell number along the exponential phase of the growth curve. ResultsThe results substantiate the outcome from the proteomic study in which ERp29 expression was significantly higher in primary osteosarcoma cells compared to osteoblastic cells. Immunohistochemical analysis found that expression of ERp29 was low in 79% of the cases (immunoreactive score (IRS) <6). A significant correlation was observed between expression of ERp29 and patient survival. Lower expression of ERp29 (IRS<6) was statistically significantly associated with shorter overall survival of the patients (P = 0.041). In addition, we found that osteosarcoma cells with low ERp29 expression had a higher growth rate compared with high-ERp29-expressing cells. ConclusionsThese findings suggest a tumor suppressive role of ERp29 in osteosarcoma. In addition, ERp29 might potentially be applied as a prognostic indicator in patients with osteosarcoma.

Expression and clinical significance of endoplasmic reticulum protein 29 and Jagged1 in gastric carcinoma

Objective To study the expression and clinical significance of endoplasmic reticulum protein 29 (ERp29) and Jagged1 in gastric carcinoma. Methods The expression levels of ERp29 and Jagged1 in 95 cases of gastric carcinoma tissues and adjacent gastric tissues (5 cm distance away from the margin of gastric carcinoma) were detected by immunohistochemical method. Results The expression rate of ERp29 in gastric carcinoma tissues was lower than that of non-cancerous adjacent gastric tissues (43.16% vs. 84.21%, t=34.614, P<0.01). The expression levels of ERp29 were related to TNM stage and lymph node metastasis of gastric carcinoma (respectively, t=4.876, 5.350, P<0.05). The expression rate of Jagged1 in gastric carcinoma tissues was lower than that of non-cancerous adjacent gastric tissues (40.00% vs. 78.95%, t=29.894, P<0.01). The expression levels of Jagged1 were related to histology grade, TNM stage and lymph node metastasis of gastric carcinoma (respectively, t=5.982, 4.498, 4.787, P<0.05). Conclusion ERp29 and Jagged1 are lowly expressed in gastric carcinoma. ERp29 and Jagged1 may be closely correlated to carcinogenesis, development and metastasis of gastric carcinoma. Key words: Gastric carcinoma; Endoplasmic reticulum protein 29; Jagged1; Immunohistochemical method

Expression of Yes-associated protein 1, endoplasmic reticulum protein 29 in colorectal carcinoma and their clinical significance

Objective To investigate the expression of Yes-associated protein 1 (Yap1), endoplasmic reticulum protein 29 (ERp29) in colorectal carcinoma and their relationship with clinicopathological features. Methods The expression levels of YAP1 and ERp29 in 85 cases of colorectal carcinoma tissues and adjacent colorectal tissues were detected by using immunohistochemical method. Results The positive rate of YAP1 expression in colorectal carcinoma tissues (61.18%, 52/85) was significantly higher than that in non-cancerous adjacent colorectal tissues (17.65%, 15/85) (t=43.731, P<0.01), the expressions of YAP1 were related colorectal carcinoma to TNM stage, lymph node metastasis (Respectively, t=6.632, 5.273, P<0.05); the positive rate of ERp29 expression in colorectal carcinoma tissues (42.35%, 36/85) was significantly lower than that in non-cancerous adjacent colorectal tissues (95.29%, 81/85) (t=55.515, P<0.01), the expressions of ERp29 were related colorectal carcinoma to TNM stage, serosa invasion, lymph node metastasis (Respectively, t=5.058, 5.472, 5.908, P<0.05). Conclusion YAP1 and ERp29 were abnormal experssion in colorectal carcinoma, Detecting the expressions of YAP1 and ERp29 simultaneously in colorectal carcinoma have certain reference value for judging invasion and metastasis potential and evaluating prognosis of patients with colorectal carcinoma. Key words: Colorectal carcinoma; Immunohistochemical Method; Yes-associated protein 1; Endoplasmic reticulum protein 29

ERp29 counteracts the suppression of malignancy mediated by endoplasmic reticulum stress and promotes the metastasis of colorectal cancer.

Endoplasmic reticulum protein 29 (ERp29), an endoplasmic reticulum (ER) protein, participates in ER stress (ERS), but little is known about the association of ERp29 with ERS in the metastasis and prognosis of cancerous diseases. The present study revealed that ERp29 was important to ERS and interfered with the malignant behaviors of colorectal cancer (CRC). Experiments in in vitro and in animal models revealed that ERS inhibited the cell growth and suppressed the metastatic capacity of CRC cells, but ERp29 counteracted these effects. Furthermore, it was demonstrated that ERp29 recovered the migration and metastatic behaviors of CRC cells suppressed by ERS, mediated only when it combined with cullin5 (CUL5). ERp29 also relied on CUL5 to promote epithelial-mesenchymal transition. From the immunohistochemical examination of CRC tissues, the high expression of ERp29 was revealed to predict the poor prognosis of 457 CRC cases. The retrospective analysis of the clinicopathological data of patients with CRC was consistent with the results of the in vitro and in vivo experiments. Thus, ERp29 protected CRC cells from ERS-mediated reduction of malignancy to promote metastasis and may be a potential target of medical intervention for CRC therapy.

Lutein and Zeaxanthin Isomers Reduce Photoreceptor Degeneration in the Pde6b rd10 Mouse Model of Retinitis Pigmentosa.

Purpose Lutein, RR-zeaxanthin, and RS-zeaxanthin (L-Z) are antioxidants which can reduce endoplasmic reticulum stress (ERS) and oxidative stress (OS), and ameliorate neurodegenerative diseases. However, their treatment effect in the Pde6brd10 (rd10) mouse model of retinitis pigmentosa (RP) and the underlying cellular mechanisms have not been studied. ERS is an important factor which causes photoreceptor apoptosis. The aim of the current project is to test the treatment effect of L-Z in rd10 mice and to investigate the underlying molecular mechanisms of ERS. Methods L-Z (Lutemax 2020, 10 mg/kg) diluted in sunflower oil (SFO, 1 mg/ml) or the same volume of SFO was administrated via gavage from postnatal day 6 (P6) to P20 daily in L-Z group (n=5) or SFO group (n=6) of rd10 mice. At P21, electroretinography (ERG) was performed to show the functional change of retinas. 78 kDa glucose-regulated protein (GRP78) and endoplasmic reticulum protein 29 (ERp29) were tested by western blot and immunostaining. Results The ERG amplitudes were larger in the L-Z group than those of the SFO group in all flash luminances of dark-adapted and light-adapted ERG (all p < 0.01). Western blot revealed that GRP78 in the retinas of the L-Z group was significantly downregulated compared to that of the SFO group (p < 0.01). Meanwhile, the retinal ERp29 protein was significantly upregulated in the L-Z treatment group than that of the SFO group (p < 0.01). Conclusions L-Z provide protection to the photoreceptors of rd10 mouse model of RP, which is probably associated with the reduction of ERS.

ERp29 downregulation enhances lung adenocarcinoma cell chemosensitivity to gemcitabine by upregulating HSP27 phosphorylation.

The aim of the current study was to assess the underlying mechanism of endoplasmic reticulum protein 29 (ERp29) in lung adenocarcinoma chemosensitivity to gemcitabine. Western blot analysis was performed to detect ERp29 expression following lung adenocarcinoma cell treatment with gemcitabine. The effects of gemcitabine in combination with ERp29 siRNA on cell apoptosis, cell cycle and heat shock protein 27 (HSP27) expression were assessed. The results demonstrated that ERp29 expression was increased on exposure to gemcitabine. The apoptotic rate of lung adenocarcinoma cells were also increased following gemcitabine treatment and the combined application of gemcitabine and ERp29 siRNA synergistically increased apoptotic rates further. It was also revealed that gemcitabine and ERp29 siRNA synergistically increased the ratio of phosphorylated to total HSP27 protein. In addition, downregulation of HSP27 significantly reduced lung adenocarcinoma chemosensitivity to gemcitabine. These data indicate that ERp29 affects lung adenocarcinoma cell chemosensitivity to gemcitabine by regulating phosphorylated HSP27. ERp29 is a novel target, which may be used to enhance the therapeutic effect of lung adenocarcinoma treatment with gemcitabine.

Molecular Chaperone ERp29: A Potential Target for Cellular Protection in Retinal and Neurodegenerative Diseases.

The molecular chaperone endoplasmic reticulum protein 29 (ERp29) plays a critical role in protein folding, trafficking, and secretion. Though ubiquitously expressed, ERp29 is upregulated in response to ER stress and is found at higher levels in certain cell types such as secretory epithelial cells and neurons. As an ER resident protein, ERp29 shares many structural and functional similarities with protein disulfide isomerases, but is not regarded as part of this family due to several key differences. The broad expression and myriad roles of ERp29 coupled with its upregulation via the unfolded protein response (UPR) upon ER stress have implicated ERp29 in a range of cellular processes and diseases. We summarize the diverse activities of ERp29 in protein trafficking, cell survival and apoptosis, and ER homeostasis and highlight a potential role of ERp29 in neuroprotection in retinal and neurodegenerative diseases.

ERp29 controls invasion and metastasis of gastric carcinoma by inhibition of epithelial-mesenchymal transition via PI3K/Aktsignaling pathway

BackgroundGastric cancer (GC) accounts for the fourth most occurring malignancy and the third major cause of cancer death. Identifying novel molecular signaling pathways participating in gastric tumorigenesis and progression is pivotal for rational design of targeted therapies to improve advanced GC outcome. Recently, the endoplasmic reticulum (ER) protein 29 (ERp29) has been shown to inversely associate with primary tumor development and function as a tumor suppressor in breast cancer. However, the role of ERp29 in GC patients’ prognosis and its function in GC progression is unknown.MethodsClinical importance of ERp29 in the prognosis of GC patients was assessed by examining its expression in 148 GC tumor samples and correlation with clinicopathological characteristics and survival of the patients. The function and underlying mechanisms of ERp29 in GC growth, invasion and metastasis were explored both in vitro and in vivo.ResultsDownregulation of ERp29 was commonly found in GC tissues and highly correlated with more aggressive phenotypes and poorer prognosis. Functional assays demonstrated that knockdown of ERp29 increased GC cell migration and invasion and promoted metastasis. Conversely, ectopic overexpression of ERp29 produced opposite effects. Mechanistic studies revealed that loss of ERp29 induced an epithelial-to-mesenchymal transition (EMT) in the GC cells through activation of PI3K/Akt pathway signaling.ConclusionThese findings suggest that downregulation of ERp29 is probably one of the key molecular mechanisms responsible for the development and progression of GC.

Proteomic identification of ERP29 as a key chemoresistant factor activated by the aggregating p53 mutant Arg282Trp.

Mutation of the TP53 gene represents a prevalent genetic alteration in human cancers, and a subset of p53 mutants may form amyloid-like aggregates that contribute to the gain of oncogenic functions (GOFs) and chemoresistance. Here we identify the pathways that may mediate the aggregation-associated GOF by using combined proteomic analysis and genome-wide recruitment profiling. Mass spectrometry revealed activation of unfolded protein response (UPR) pathway and upregulation of endoplasmic reticulum protein 29 (ERp29) in R282WTP53-expressing cells that were exposed to cisplatin stress. Chromatin immunoprecipitation sequencing identified a significant 'CCCASS' binding motif of Arg282Trp, which is present in the promoter region of ERP29 gene. The mutant p53 upregulated ERP29 mRNA and protein expression levels, whereas targeting ERP29 by specific small interfering RNAs suppressed the chemoresistant effect of Arg282Trp. The anti-aggregation peptide ReACp53 significantly decreased ERP29 expression and suppressed the chemoresistant effect. These findings highlight a role of ERP29 in the acquired chemoresistance of cancer cells expressing the aggregating p53 mutant Arg282Trp. Our results also suggest that ERP29-mediated GOF can be targeted by the anti-aggregation peptide ReACp53.

Erp29 Attenuates Cigarette Smoke Extract-Induced Endoplasmic Reticulum Stress and Mitigates Tight Junction Damage in Retinal Pigment Epithelial Cells.

Endoplasmic reticulum protein 29 (ERp29) is a novel chaperone that was recently found decreased in human retinas with AMD. Herein, we examined the effect of ERp29 on cigarette smoke-induced RPE apoptosis and tight junction disruption. Cultured human RPE (HRPE) cells (ARPE-19) or mouse RPE eyecup explants were exposed to cigarette smoke extract (CSE) for short (up to 24 hours) or long (up to 3 weeks) periods. Expression of ERp29 was up- and downregulated by adenovirus and siRNA, respectively. Endoplasmic reticulum stress markers, apoptosis, and cell death, the expression and distribution of tight junction protein ZO-1, transepithelial electrical resistance (TEER), and F-actin expression were examined. Endoplasmic reticulum protein 29 was significantly increased by short-term exposure to CSE in ARPE-19 cells or eyecup explants but was reduced after 3-week exposure. Overexpression of ERp29 increased the levels of GRP78, p58(IPK), and Nrf-2, while reducing p-eIF2α and C/EBP homologous protein (CHOP), and protected RPE cells from CSE-induced apoptosis. In contrast, knockdown of ERp29 decreased the levels of p58(IPK) and Nrf2, but increased p-eIF2α and CHOP and exacerbated CSE-triggered cell death. In addition, overexpression of ERp29 attenuated CSE-induced reduction in ZO-1 and enhanced the RPE barrier function, as measured by TEER. Knockdown of ERp29 decreased the level of ZO-1 protein. These effects were associated with changes in the expression of cytoskeleton F-actin. Endoplasmic reticulum protein 29 attenuates CSE-induced ER stress and enhances cell viability and barrier integrity of RPE cells, and therefore may act as a protective mechanism for RPE survival and activity.

Endoplasmic reticulum protein 29 (ERp29) confers radioresistance through the DNA repair gene, O(6)-methylguanine DNA-methyltransferase, in breast cancer cells.

Resistance of cancer cells to radiotherapy is a major clinical problem in cancer treatment. Therefore, understanding the molecular basis of cellular resistance to radiotherapy and identification of novel targets are essential for improving treatment efficacy for cancer patients. Our previous studies have demonstrated a significant role of ERp29 in breast cancer cell survival against doxorubicin-induced genotoxic stress. We here reported that ERp29 expression in the triple negative MDA-MB-231 breast cancer cells significantly increased cell survival against ionizing radiation. Methylation PCR array analysis identified that ERp29 expression increased promoter hypomethylation of the DNA repair gene, O6-methylguanine DNA-methyltransferase (MGMT), by downregulating DNA methyltransferase 1. Knockdown of MGMT in the ERp29-transfected cancer cells increased radiosensitivity, leading to a decreased post-irradiation survival. In addition, radiation treatment in the MGMT-knockdown cells elevated phosphorylation of γ-H2AX and cleavage of caspase 3, indicating that depletion of MGMT facilitates DNA double strands breaks and increases cell apoptosis. Hence, our studies prove a novel function of ERp29\\MGMT in cancer cell survival against radiation. Targeting ERp29\\MGMT axis may be useful for providing better treatment efficacy in combination with radiotherapy in breast cancer.

Increased expression of endoplasmic reticulum protein 29 in lung adenocarcinoma is associated with chemosensitivity to gemcitabine.

Lung adenocarcinoma is the leading cause of cancer-related death worldwide. The aim of the present study was to investigate the potential function of endoplasmic reticulum protein 29 (ERp29) in lung adenocarcinoma. We examined the expression of ERp29 in 75 patients with lung adenocarcinoma by immunohistochemical analysis, as well as its association with clinicopathological features. We further tested the effects of inhibiting ERp29 on cell proliferation, migration ability, and chemosensitivity to gemcitabine in human lung adenocarcinoma cell lines. ERp29 was significantly overexpressed in lung adenocarcinoma when compared with matched nontumor tissues. However, we did not observe significant associations of ERp29 with any of the clinicopathologic characteristics, including sex, age, differentiation, tumor, node, and metastasis stage, T stage, and lymph node metastasis. Downregulation of ERp29 by small interfering RNA did not affect cell growth, but impaired cell migration of lung adenocarcinoma cells. Inhibition of ERp29 significantly enhanced the chemosensitivity of lung adenocarcinoma cells to gemcitabine. These results support a probable treatment combination of gemcitabine and inhibition of ERp29 overexpression for lung adenocarcinoma to promote the clinical curative effects.

Fucoidan induces cancer cell apoptosis by modulating the endoplasmic reticulum stress cascades.

BackgroundCancer metastasis is the main cause leading to disease recurrence and high mortality in cancer patients. Therefore, inhibiting metastasis process or killing metastatic cancer cells by inducing apoptosis is of clinical importance in improving cancer patient survival. Previous studies revealed that fucoidan, a fucose-rich polysaccharide isolated from marine brown alga, is a promising natural product with significant anti-cancer activity. However, little is known about the role of endoplasmic reticulum (ER) stress in fucoidan-induced cell apoptosis.Principal FindingsWe reported that fucoidan treatment inhibits cell growth and induces apoptosis in cancer cells. Fucoidan treatments resulted in down-regulation of the glucose regulated protein 78 (GRP78) in the metastatic MDA-MB-231 breast cancer cells, and of the ER protein 29 (ERp29) in the metastatic HCT116 colon cancer cells. However, fucoidan treatment promoted ER Ca2+-dependent calmodulin-dependent kinase II (CaMKII) phosphorylation, Bcl-associated X protein (Bax) and caspase 12 expression in MDA-MB-231 cells, but not in HCT116 cells. In both types of cancer cells, fucoidan activated the phosphorylation of eukaryotic initiation factor 2 alpha (p-eIF2α)\\CCAAT/enhancer binding protein homologous protein (CHOP) pro-apoptotic cascade and inhibited the phosphorylation of inositol-requiring kinase 1 (p-IRE-1)\\X-box binding proteins 1 splicing (XBP-1s) pro-survival cascade. Furthermore, CHOP knockdown prevented DNA damage and cell death induced by fucoidan.Conclusion/SignificanceFucoidan exerts its anti-tumor function by modulating ER stress cascades. Contribution of ER stress to the fucoidan-induced cell apoptosis augments our understanding of the molecular mechanisms underlying its anti-tumour activity and provides evidence for the therapeutic application of fucoidan in cancer.