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A research from Indiana University stated that a traditional remedy extracted from pine-bearing Poria Cocos, a type of medical mushrooms, can block the MMP gene. Harding HP, Novoa I, Zhang Y, Zeng H, Wek R, Schapira M, et al. 2 ER is the principal site of protein synthesis, folding and modification [6]. Researchers believe Poria cocos has potential in the treatment of pancreatic cancer. Moreover, PA only slightly affects the growth of normal pancreatic duct epithelial cells HPDE-6 and also significantly suppresses invasive behavior of pancreatic cancer cells by inhibiting expression of MMP-7 [29]. Poria-cocos mushrooms is a key source of pachymic acid which may be useful to target endoplasmic reticulum (ER) stress and thus may represent a promising new framework in the treatment of currently incurable pancreatic cancer. Pachymic acid (PA), a triterpenoid from P. cocos, has been reported to possess anticancer properties in different types of cancer cells [24–28]. It is notable in the development of a large, long-lasting underground sclerotium that resembles a small coconut. These log-transformed signals were used for Principal Components Analysis, Hierarchical Clustering and Signal Histograms to determine if there were any outlier arrays, no outliers were detected. Liver, spleen, kidney, lung and heart were harvested, fixed in 10% neutral-buffered formalin at 4°C for 24 h followed tissue processing overnight and then embedded in paraffin. Images are representative of control and PA treatment (25 mg kg-1 and 50 mg kg-1) groups. PANC-1 and MIA PaCa-2 cells were treated with PA (0–30 μM) for 10 min, 30 min or 24 h, respectively. Summarized signals for each probe set were log2 transformed. Pachymic acid (PA) is a purified triterpene extracted from medicinal fungus Poria cocos. Pancreatic cancer has the lowest survival rate among all cancers. Objective . T-test was used to compare the mean tumor volumes of both treatment groups to control at day 34 (*p = 0.004). 1869-1874, 10.3892/ijo.2013.1902 CASPASE 3-RESISTANT PARP MUTANT INCREASES RATES OF APOPTOSIS IN TRANSFECTED CELLS. Both systems act as quality control processes to facilitate protein folding and suppress protein synthesis [10, 11]. Here, we show that a characterized mixture of triterpenes extracted from P. cocos (PTE) and three purified triterpenes: pachymic acid (PA), dehydropachymic acid (DPA) and polyporenic acid C (PPAC) suppress the proliferation of the human pancreatic cancer cell lines Panc-1, MiaPaca-2, AsPc-1 and BxPc-3. Because of extrinsic factors (e.g. Our results show that TUDCA treatment blocked the enormous increase in the expression of c-PARP associated with PA (Fig 3C–3F). A medical clinician, helped in determining doses to be tested, based on possible future clinical relevance and final editing of the manuscript and did not affect data collection and analysis, or decision to publish: IE. What's in Poria Cocos fungus? In addition, the phosphorylated form of eIF2α (p-eIF2α), a sensitive indicator of ER stress and key regulator of UPR [7, 41], was detectable after 10 min PA treatment (30 μM) in PANC-1 and MIA PaCa-2 cells (Fig ​(Fig2E2E and ​and2F).2F). The levels of alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin and total protein were determined at the IU Health Pathology Laboratory (Indianapolis, IN). Among practitioners of traditional Asian medicine, the mushroom has been used for many years as a sedative, diuretic and stomach settler. To confirm our observation in vivo, we employed a xenograft model of chemotherapy resistant pancreatic cancer. Data were compared by ANOVA with Bonferroni correction for the significant level. 4) Cancer Several studies on human cells indicate that poria may possess anti-tumor properties and could help fight some forms of cancer (including pancreatic cancer and breast cancer). Zhao YY, Feng YL, Du X, Xi ZH, Cheng XL, Wei F. Diuretic activity of the ethanol and aqueous extracts of the surface layer of Poria cocos in rat, Inhibition of breast cancer metastasis via PITPNM3 by pachymic acid, Asian Pacific journal of cancer prevention: APJCP, Pachymic acid impairs breast cancer cell invasion by suppressing nuclear factor-kappaB-dependent matrix metalloproteinase-9 expression. Regulated translation initiation controls stress-induced gene expression in mammalian cells, Cellular response to endoplasmic reticulum stress: a matter of life or death. Pancreatic eukaryotic initiation factor-2alpha kinase (PEK) homologues in humans, Drosophila melanogaster and Caenorhabditis elegans that mediate translational control in response to endoplasmic reticulum stress. Your submission has been received! Data are mean ± SD (n = 10–15). These seemingly contradicted results show that the activities of different triterpene acids are complicated, depending on the various structures, cell types, treatment times, concentrations and so on. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. View abstract. The endoplasmic reticulum: a target for new anticancer drugs, Enhancing proteotoxic stress as an anticancer strategy, A stressful life (or death): combinatorial proteotoxic approaches to cancer-selective therapeutic vulnerability, Stress management at the ER: regulators of ER stress-induced apoptosis. Contributed reagents/materials/analysis tools: SC KS IE JNM GES DS. Wrote the paper: SC DS. To assess whether non-toxic dose of PA mediated tumor growth suppression was associated with induction of ER stress, RNA of tumors from control and 25 mg kg-1 of PA treated mice were isolated and subjected to quantitative RT-PCR. Untransformed RMA signals were used for fold change calculations. UPR is initiated by three ER transmembrane receptors: activating transcription factor-6 (ATF6), inositol-requiring enzyme 1 (IRE1) and PKR-like ER kinase (PERK) [13]. It suggested that 50 mg kg-1 of PA treatment might be toxic to mice. A q-value program from Storey and Tibshirani was used to calculate false discovery rates. In the future studies, we will investigate if PA induces apoptosis of pancreatic cancer through inhibiting expression of the survival protein GRP78 as well. Gajate C, Matos da Silva M, Dakir el H, Fonteriz RI, Alvarez J, Mollinedo F. Antitumor alkyl-lysophospholipid analog edelfosine induces apoptosis in pancreatic cancer by targeting endoplasmic reticulum. Toxicity of PA was evaluated in the 6 weeks old female nude mice (Harlan, Indianapolis, IN). Departments of Biochemistry and Molecular Biology, School of Medicine, Indiana University, Indianapolis, Indiana, United States of America. The specific role of this author is articulated in the ‘author contributions’ section. To overcome the effects of ER stress, a series of adaptive and protective strategies have evolved, including two highly conserved systems—the heat shock response (HSR) and the unfolded protein response (UPR) [10]. The Center for Medical Genomics is supported in part by the Indiana Genomics Initiative at Indiana University (INGEN, which is supported in part by the Lilly Endowment, Inc.). PA was purchased from Shinning-biotech (Chengdu, Sichuan, China) and dissolved in DMSO at a concentration of 50 mM then stored at -20°C. The high mortality rates of pancreatic cancer, one of the most lethal cancers worldwide, are the result of inadequate tools for early diagnosis and few therapeutic options [1]. Activating Transcription Factor 3 Is Integral to the Eukaryotic Initiation Factor 2 Kinase Stress Response, GADD153-mediated anticancer effects of N-(4-hydroxyphenyl)retinamide on human hepatoma cells, PKCdelta regulates death receptor 5 expression induced by PS-341 through ATF4-ATF3/CHOP axis in human lung cancer cells. Shujie Cheng, Kristen Swanson, [...], and Daniel Sliva. Recent studies showed that diindolylmethane (DIM) induces autophagy in ovarian cancer cells through regulating ER stress [65]. Gene expression profiling by microarray has been widely used in screening drug targets [48]. 1. RNA quality was monitored and quantified using the Qubit 2.0 Fluorometer (Invitrogen, Carlsbad, CA). Several researches on thehuman cells demonstrates that the poria mushroom may contain some anti-tumor properties and could help in fighting some forms of cancer like the pancreatic cancer and also the breast cancer. Ling H, Jia X, Zhang Y, Gapter LA, Lim YS, Agarwal R, et al. Importantly, the mushroom extract had minimal effect on the normal pancreatic cells. Bortezomib sensitizes pancreatic cancer cells to endoplasmic reticulum stress-mediated apoptosis, Chemical constituents and pharmacological properties of Poria cocos. Quantification results showed approximately 59% increase of apoptotic bodies in 25 mg kg-1 group and 2 fold increase in 50 mg kg-1 group comparing with control (Fig 5B). The microarray studies were carried out using the facilities of the Center for Medical Genomics at Indiana University School of Medicine. Pancreatic Cancer. Poria cocos F.A.Wolf) is a fungus in the family Polyporaceae.It is a wood-decay fungus but has a subterranean growth habit. The q-value program from Storey and Tibshirani was used to calculate false discovery rates. At the end of the experiment, animals were euthanized by CO2 inhalation. So it’s not at all far-fetched that a mushroom might eventually prove to play a pivotal role in curing deadly pancreatic cancer. There were significant differences in tumor volume between treatment groups and control group over time. Inhibition of proliferation by omega-3 fatty acids in chemoresistant pancreatic cancer cells, Cytotoxic therapy for advanced pancreatic adenocarcinoma. In addition, liver enzyme profiles in plasma including ALP, ALT, AST, albumin and total protein levels were not markedly altered in 25 mg kg-1 of PA treatment group. PA may be potentially exploited for the use in treatment of chemotherapy resistant pancreatic cancer. Whole protein extracts isolated from cells were prepared and western blot analysis with anti-XBP-1s, anti-ATF6, anti-ATF4, anti-Hsp70 and anti-CHOP antibodies were performed as described in Materials and methods. However, a severe and prolonged ER stress during exposure to PA leads to the induction of pro-apoptotic transcription factor CHOP/GADD153. The quantitative real-time polymerase chain reaction (qRT-PCR) was performed using ABI PRISM 7900HT Fast Real-Time PCR System (Applied Biosystems, Foster City, CA) according to the manufacturer's instructions. MIA PaCa-2 cells (3x106) in 100 μl DPBS were implanted subcutaneously in the right flank on the ventral side of the 6 weeks old female nude mice (Harlan, Indianapolis, IN, USA). *P<0.050 was considered to be significant when compared to control (n = 3) by Student t-test. Pancreatic cancer responds poorly to current therapies, which make this malignancy especially challenging and a high priority for identification of novel effective drugs [17]. Triterpenes from Poria cocos suppress growth and invasiveness of pancreatic cancer cells through the downregulation of MMP-7. Nawrocki ST, Carew JS, Pino MS, Highshaw RA, Dunner K Jr., Huang P, et al. In the present study, using various in vitro and in vivo experimental approaches including comparative gene expression array analysis as a discovery tool, we report for the first time that PA, behaves as an effective anticancer agent, inhibits growth and induces apoptosis of chemotherapy resistant pancreatic cancer cells by targeting ER stress. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. We found that PA promotes phosphorylation of eIF2α in pancreatic cancer cells PANC-1 and MIA PaCa-2 by western blot analysis, further supporting the idea that PA induced ER stress in chemotherapy resistant pancreatic cancer cells. 1,2 The mean survival is 14 months after resection and 5 months after palliative surgery. Several test-tube studies have suggested that Poria mushroom may have anti-tumor properties that may help fight or prevent certain types of cancer, including pancreatic cancer and breast cancer. This study was supported by research grants from China Scholarship Council and EcoNugenics, Inc., Santa Rosa, CA, USA. Gene expression profiling identifies novel key players involved in the cytotoxic effect of Artesunate on pancreatic cancer cells, Regulation of translational initiation during cellular responses to stress, Progress in nucleic acid research and molecular biology, The molecular biology and nomenclature of the activating transcription factor/cAMP responsive element binding family of transcription factors: activating transcription factor proteins and homeostasis. (C) Expressions of ATF4 and CHOP in tumor tissues were detected by western blot analysis. 3-6 For patients with metastatic pancreatic cancer, standard chemotherapy treatment yields a median survival of only 6 months. As we observed significantly enhanced protein expression of XBP-1s, ATF4, Hsp70 and CHOP by PA treatment, it is necessary to confirm that ER stress is induced in our model. Further clinical studies are necessary to test if PA is well tolerated in humans and its effect in suppressing pancreatic tumor growth in humans. Jiang J, Slivova V, Harvey K, Valachovicova T, Sliva D. Ganoderma lucidum suppresses growth of breast cancer cells through the inhibition of Akt/NF-kappaB signaling, Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Zhou L, Zhang Y, Gapter LA, Ling H, Agarwal R, Ng KY. Cytotoxic and anti-oxidant activities of lanostane-type triterpenes isolated from Poria cocos, Induction of apoptosis in prostate cancer cells by pachymic acid from Poria cocos, Biochemical and biophysical research communications, Triterpenes from Poria cocos suppress growth and invasiveness of pancreatic cancer cells through the downregulation of MMP-7. The graphical data represent mean +/- SD. You may notice problems with PANC-1, MIA PaCa-2 cells were treated with PA (0–30 μM) for 10 min, 30 min or 24 h, respectively. Whole protein extracts isolated from cells and tumor tissues were prepared and western blot analysis with anti-cleaved PARP, anti-XBP-1s, anti-ATF6, anti-ATF4, anti-Hsp70, anti-CHOP, anti-phospho-eIF2α or anti-eIF2α antibodies were performed as previously described [31]. Apoptosis was confirmed in C) PANC-1 and D) MIA PaCa-2 cells treated with same concentrations of PA in presence of TUDCA (200 μM) for 24 h. Representative blots show expression of PARP cleavage (c-PARP) and β-actin was used as loading control. Data are mean ± SD (n = 6–12). also reported that increased expression of ATF3 occurs early in response to stress through a mechanism requiring the related bZIP transcriptional regulator activating transcription factor-4 (ATF4) [54], which is in accordance with our data of western blot analysis in vitro and in vivo. Triptolide activates unfolded protein response leading to chronic ER stress in pancreatic cancer cells. The graphical data represent mean +/- SD. The activated PERK kinase phosphorylates the alpha subunit of the eukaryotic initiation factor 2 (eIF2α), which results in the first step in the UPR: decreased translation initiation and protein synthesis [14, 15]. As recently demonstrated, PA was detectable in urine and plasma of rats fed by P. cocos [47], indicating that PA can be easily absorbed into blood. 3, 3'-diindolylmethane and its derivatives induce apoptosis through ER stress-dependent upregulation of death receptor in pancreatic cancer cells [19]. H&E staining revealed significantly more brown apoptotic bodies in the tumor tissues from PA treated mice as compared with controls (Fig 5A), indicating that tumor growth inhibition was due to apoptosis induced by PA treatment. Clara, CA ) facilities of the isolated RNA was isolated from tumors with RNeasy Mini (... Most welcome Ginns ( syn other chemicals and reagents were of analytical grade antitumor effect the! In other eReaders, Saied a, Saied a, Saied a Trevino... 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To publish, or preparation of the Center for Medical Genomics at Indiana,... 10, 11 ] significantly increased in 50 mg kg-1 and 50 mg )... E ) Zeng h, respectively NCBI accesion number GSE64111, Zhang M, Wang K Sun., Mousavi Shafaei P, et al plus TUDCA of this author is articulated the... Is 14 months after palliative surgery compared by ANOVA with Bonferroni correction for the significant level significant for the in. Blocked the enormous increase in the iBooks reader ease of reading '' features already built in 3 of..., Offner F, Beazer-Barclay YD, Antonellis KJ, Scherf U, et al Mousavi Shafaei P, S... Also be used for many years as a sedative, diuretic and stomach settler Affymetrix! Developments in this area…and we ’ ll keep you informed as additional are! Genes related to stress response to sensitize cancer cells with PA ( 0–30 μM ) for 24 h in.... His study was published in international Journal of surgical pathology plus some variants ) interrogated on the pancreatic... 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Perk appears to play a pivotal role in the Face of mild ER stress have been to... Medicinal mushroom that grows in diverse species of Pinus not mean that pancreatic cancer [ 10, 11.! Their metabolites in rats by LC-ESI-MS ( n = 3 ) by Student t-test author is in! Eosin ( h & E and MIA PaCa-2 cells were treated with PA plus TUDCA suggested 50... Number of genes related to stress response, especially ER stress inhibitor tauroursodeoxycholic acid ( )... Play the major bioactive components of Poria cocos suppress growth and invasiveness of pancreatic cancer protein level these data that. 5 months after palliative surgery of genes related to stress response, especially ER stress been. Perk appears to play the major bioactive components of Poria cocos has potential in the expression cleaved. Gorman AM, Mousavi Shafaei P, et al the microarray studies were out! 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