Targeting ER stress in the hepatic tumor microenvironment.
ER stress
fibrosis
hepatocellular carcinoma
tumor microenvironment
unfolded protein response
Journal
The FEBS journal
ISSN: 1742-4658
Titre abrégé: FEBS J
Pays: England
ID NLM: 101229646
Informations de publication
Date de publication:
11 2022
11 2022
Historique:
revised:
13
07
2021
received:
31
05
2021
accepted:
30
07
2021
pubmed:
1
8
2021
medline:
18
11
2022
entrez:
31
7
2021
Statut:
ppublish
Résumé
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. It currently ranks as one of the most aggressive and deadly cancers worldwide, with an increasing mortality rate and limited treatment options. An important hallmark of liver pathologies, such as liver fibrosis and HCC, is the accumulation of misfolded and unfolded proteins in the lumen of the endoplasmic reticulum (ER), which induces ER stress and leads to the activation of the unfolded protein response (UPR). Upon accumulation of misfolded proteins, ER stress is sensed through three transmembrane proteins, IRE1α, PERK, and ATF6, which trigger the UPR to either alleviate ER stress or induce apoptosis. Increased expression of ER stress markers has been widely shown to correlate with fibrosis, inflammation, drug resistance, and overall HCC aggressiveness, as well as poor patient prognosis. While preclinical in vivo cancer models and in vitro approaches have shown promising results by pharmacologically targeting ER stress mediators, the major challenge of this therapeutic strategy lies in specifically and effectively targeting ER stress in HCC. Furthermore, both ER stress inducers and inhibitors have been shown to ameliorate HCC progression, adding to the complexity of targeting ER stress players as an anticancer strategy. More studies are needed to better understand the dual role and molecular background of ER stress in HCC, as well as its therapeutic potential for patients with liver cancer.
Substances chimiques
Endoribonucleases
EC 3.1.-
Protein Serine-Threonine Kinases
EC 2.7.11.1
Types de publication
Journal Article
Review
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
7163-7176Informations de copyright
© 2021 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.
Références
Heindryckx F & Gerwins P (2015) Targeting the tumor stroma in hepatocellular carcinoma. World J Hepatol 7, 165-176.
Hernandez-Gea V, Toffanin S, Friedman SL & Llovet JM (2013) Role of the microenvironment in the pathogenesis and treatment of hepatocellular carcinoma. Gastroenterology 144, 512-527.
Faivre S, Rimassa L & Finn RS (2020) Molecular therapies for HCC: looking outside the box. J Hepatol 72, 342-352.
Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim T-Y, Kudo M, Breder V, Merle P, Kaseb AO et al. (2020) Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med 382, 1894-1905.
Walter P & Ron D (2011) The unfolded protein response: from stress pathway to homeostatic regulation. Science 334, 1081-1086.
Verfaillie T, Garg AD & Agostinis P (2013) Targeting ER stress induced apoptosis and inflammation in cancer. Cancer Lett 332, 249-264.
Pavlovic N, Calitz C, Thanapirom K, Mazza G, Rombouts K, Gerwins P & Heindryckx F (2020) Inhibiting IRE1alpha-endonuclease activity decreases tumor burden in a mouse model for hepatocellular carcinoma. eLife 9, e55865.
Cho H-Y, Thomas S, Golden EB, Gaffney KJ, Hofman FM, Chen TC, Louie SG, Petasis NA & Schönthal AH (2009) Enhanced killing of chemo-resistant breast cancer cells via controlled aggravation of ER stress. Cancer Lett 282, 87-97.
Hetz C, Chevet E & Harding HP (2013) Targeting the unfolded protein response in disease. Nat Rev Drug Discov 12, 703-719.
McCarthy N, Dolgikh N, Logue S, Patterson JB, Zeng Q, Gorman AM, Samali A & Fulda S (2020) The IRE1 and PERK arms of the unfolded protein response promote survival of rhabdomyosarcoma cells. Cancer Lett 490, 76-88.
Cubillos-Ruiz JR, Bettigole SE & Glimcher LH (2017) Tumorigenic and immunosuppressive effects of endoplasmic reticulum stress in cancer. Cell 168, 692-706.
Gardner BM & Walter P (2011) Unfolded proteins are Ire1-activating ligands that directly induce the unfolded protein response. Science 333, 1891-1894.
Hetz C (2012) The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat Rev Mol Cell Biol 13, 89-102.
Wu J, He GT, Zhang WJ, Xu J & Huang QB (2016) IRE1alpha signaling pathways involved in mammalian cell fate determination. Cell Physiol Biochem 38, 847-858.
Logue SE, McGrath EP, Cleary P, Greene S, Mnich K, Almanza A, Chevet E, Dwyer RM, Oommen A, Legembre P et al. (2018) Inhibition of IRE1 RNase activity modulates the tumor cell secretome and enhances response to chemotherapy. Nat Commun 9, 3267.
Raymundo DP, Doultsinos D, Guillory X, Carlesso A, Eriksson LA & Chevet E (2020) Pharmacological targeting of IRE1 in cancer. Trends Cancer 6, 1018-1030.
Luo DH, He Y, Zhang HF, Yu LY, Chen H, Xu Z, Tang SB, Urano F & Min W (2008) AIP1 is critical in transducing IRE1-mediated endoplasmic reticulum stress response. J Biol Chem 283, 11905-11912.
Tam AB, Mercado EL, Hoffmann A & Niwa M (2012) ER stress activates NF-kappaB by integrating functions of basal IKK activity, IRE1 and PERK. PLoS One 7, e45078.
Garg AD, Kaczmarek A, Krysko O, Vandenabeele P, Krysko DV & Agostinis P (2012) ER stress-induced inflammation: does it aid or impede disease progression? Trends Mol Med 18, 589-598.
Cullinan SB, Zhang D, Hannink M, Arvisais E, Kaufman RJ & Diehl JA (2003) Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival. Mol Cell Biol 23, 7198-7209.
Cullinan SB & Diehl JA (2004) PERK-dependent activation of Nrf2 contributes to redox homeostasis and cell survival following endoplasmic reticulum stress. J Biol Chem 279, 20108-20117.
Ji C, Kaplowitz N, Lau MY, Kao E, Petrovic LM & Lee AS (2011) Liver-specific loss of glucose-regulated protein 78 perturbs the unfolded protein response and exacerbates a spectrum of liver diseases in mice. Hepatology 54, 229-239.
Malhi H & Kaufman RJ (2011) Endoplasmic reticulum stress in liver disease. J Hepatol 54, 795-809.
Al-Rawashdeh FY, Scriven P, Cameron IC, Vergani PV & Wyld L (2010) Unfolded protein response activation contributes to chemoresistance in hepatocellular carcinoma. Eur J Gastroenterol Hepatol 22, 1099-1105.
Shuda M, Kondoh N, Imazeki N, Tanaka K, Okada T, Mori K, Hada A, Arai M, Wakatsuki T, Matsubara O et al. (2003) Activation of the ATF6, XBP1 and grp78 genes in human hepatocellular carcinoma: a possible involvement of the ER stress pathway in hepatocarcinogenesis. J Hepatol 38, 605-614.
Chava S, Lee C, Aydin Y, Chandra PK, Dash A, Chedid M, Thung SN, Moroz K, Wu T, Nayak NC et al. (2017) Chaperone-mediated autophagy compensates for impaired macroautophagy in the cirrhotic liver to promote hepatocellular carcinoma. Oncotarget 8, 40019-40036.
Gu X, Li K, Laybutt DR, He ML, Zhao HL, Chan JC & Xu G (2010) Bip overexpression, but not CHOP inhibition, attenuates fatty-acid-induced endoplasmic reticulum stress and apoptosis in HepG2 liver cells. Life Sci 87, 724-732.
Tang J, Guo YS, Zhang Y, Yu XL, Li L, Huang W, Li Y, Chen B, Jiang J-L & Chen Z-N (2012) CD147 induces UPR to inhibit apoptosis and chemosensitivity by increasing the transcription of Bip in hepatocellular carcinoma. Cell Death Differ 19, 1779-1790.
Lebeaupin C, Vallee D, Hazari Y, Hetz C, Chevet E & Bailly-Maitre B (2018) Endoplasmic reticulum stress signalling and the pathogenesis of non-alcoholic fatty liver disease. J Hepatol 69, 927-947.
Pavlović N & Heindryckx F (2021) Exploring the role of endoplasmic reticulum stress in hepatocellular carcinoma through the mining of the human protein atlas. Biology 10, 640.
Jin C, Jin Z, Chen NZ, Lu M, Liu CB, Hu WL & Zheng CG (2016) Activation of IRE1alpha-XBP1 pathway induces cell proliferation and invasion in colorectal carcinoma. Biochem Biophys Res Commun 470, 75-81.
Fang PP, Xiang LX, Huang SS, Jin LX, Zhou GY, Lu ZG, Jie L, Fan H, Zhou L, Pan C et al. (2018) IRE1-XBP1 signaling pathway regulates IL-6 expression and promotes progression of hepatocellular carcinoma. Oncol Lett 16, 4729-4736.
Henkel A & Green RM (2013) The unfolded protein response in fatty liver disease. Semin Liver Dis 33, 321-329.
Tiniakos DG, Mauricio J & Reeves HL (2018) Fatty liver disease and hepatocellular carcinoma: the pathologist's view. Adv Exp Med Biol 1032, 55-69.
Heindryckx F, Binet F, Ponticos M, Rombouts K, Lau J, Kreuger J & Gerwins P (2016) Endoplasmic reticulum stress enhances fibrosis through IRE1 alpha-mediated degradation of miR-150 and XBP-1 splicing. EMBO Mol Med 8, 729-744.
Wu Y, Shan B, Dai J, Xia Z, Cai J, Chen T, Lv S, Feng Y, Zheng L, Wang Y et al. (2018) Dual role for inositol-requiring enzyme 1alpha in promoting the development of hepatocellular carcinoma during diet-induced obesity in mice. Hepatology 68, 533-546.
Li X, Zhu H, Huang H, Jiang R, Zhao W, Liu Y, Zhou J & Guo FJ (2012) Study on the effect of IRE1a on cell growth and apoptosis via modulation PLK1 in ER stress response. Mol Cell Biochem 365, 99-108.
Bobrovnikova-Marjon E, Grigoriadou C, Pytel D, Zhang F, Ye J, Koumenis C, Cavener D & Diehl JA (2010) PERK promotes cancer cell proliferation and tumor growth by limiting oxidative DNA damage. Oncogene 29, 3881-3895.
Vandewynckel YP, Laukens D, Bogaerts E, Paridaens A, Van den Bussche A, Verhelst X, Van Steenkiste C, Descamps B, Vanhove C, Libbrecht L et al. (2015) Modulation of the unfolded protein response impedes tumor cell adaptation to proteotoxic stress: a PERK for hepatocellular carcinoma therapy. Hepatol Int 9, 93-104.
Rojas-Rivera D, Delvaeye T, Roelandt R, Nerinckx W, Augustyns K, Vandenabeele P & Bertrand MJM (2017) When PERK inhibitors turn out to be new potent RIPK1 inhibitors: critical issues on the specificity and use of GSK2606414 and GSK2656157. Cell Death Differ 24, 1100-1110.
Zhou B, Lu QQ, Liu JT, Fan LL, Wang Y, Wei W, Wang H, & Sun G (2019) Melatonin increases the sensitivity of hepatocellular carcinoma to sorafenib through the PERK-ATF4-Beclin1 pathway. Int J Biol Sci 15, 1905-1920.
Vandewynckel YP, Coucke C, Laukens D, Devisscher L, Paridaens A, Bogaerts E, Vandierendonck A, Raevens S, Verhelst X, Van Steenkiste C et al. (2016) Next-generation proteasome inhibitor oprozomib synergizes with modulators of the unfolded protein response to suppress hepatocellular carcinoma. Oncotarget 7, 34988-35000.
Li D, Wang WJ, Wang YZ, Wang YB & Li YL (2019) Lobaplatin promotes (125)I-induced apoptosis and inhibition of proliferation in hepatocellular carcinoma by upregulating PERK-eIF2alpha-ATF4-CHOP pathway. Cell Death Dis 10, 744.
Chen YJ, Su JH, Tsao CY, Hung CT, Chao HH, Lin JJ, Liao MH, Yang ZY, Huang HH, Tsai FJ et al. (2013) Sinulariolide induced hepatocellular carcinoma apoptosis through activation of mitochondrial-related apoptotic and PERK/eIF2 alpha/ATF4/CHOP pathway. Molecules 18, 10146-10161.
Li J, Zhuo JY, Zhou W, Hong JW, Chen RG, Xie HY, Zhou L, Zheng SS & Jiang DH (2020) Endoplasmic reticulum stress triggers delanzomib-induced apoptosis in HCC cells through the PERK/eIF2alpha/ATF4/CHOP pathway. Am J Transl Res 12, 2875-2889.
Yu CL, Yang SF, Hung TW, Lin CL, Hsieh YH & Chiou HL (2019) Inhibition of eIF2alpha dephosphorylation accelerates pterostilbene-induced cell death in human hepatocellular carcinoma cells in an ER stress and autophagy-dependent manner. Cell Death Dis 10, 418.
Arai M, Kondoh N, Imazeki N, Hada A, Hatsuse K, Kimura F, Matsubara O, Mori K, Wakatsuki T & Yamamoto M (2006) Transformation-associated gene regulation by ATF6alpha during hepatocarcinogenesis. FEBS Lett 580, 184-190.
Scaiewicz V, Nahmias A, Chung RT, Mueller T, Tirosh B & Shibolet O (2013) CCAAT/enhancer-binding protein homologous (CHOP) protein promotes carcinogenesis in the DEN-induced hepatocellular carcinoma model. PLoS One 8, e81065.
Bu LJ, Yu HQ, Fan LL, Li XQ, Wang F, Liu JT, Zhong F, Zhang C-J, Wei W, Wang H et al. (2017) Melatonin, a novel selective ATF-6 inhibitor, induces human hepatoma cell apoptosis through COX-2 downregulation. World J Gastroenterol 23, 986-998.
Tsuchida T & Friedman SL (2017) Mechanisms of hepatic stellate cell activation. Nat Rev Gastroenterol Hepatol 14, 397-411.
Amann T, Bataille F, Spruss T, Muhlbauer M, Gabele E, Scholmerich J, Kiefer P, Bosserhoff A-K & Hellerbrand C (2009) Activated hepatic stellate cells promote tumorigenicity of hepatocellular carcinoma. Cancer Sci 100, 646-653.
Barry AE, Baldeosingh R, Lamm R, Patel K, Zhang K, Dominguez DA, Kirton KJ, Shah AP & Dang H (2020) Hepatic stellate cells and hepatocarcinogenesis. Front Cell Dev Biol 8, 709.
Koo JH, Lee HJ, Kim W & Kim SG (2016) Endoplasmic reticulum stress in hepatic stellate cells promotes liver fibrosis via PERK-mediated degradation of HNRNPA1 and up-regulation of SMAD2. Gastroenterology 150, 181-193.e8.
Liu ZK, Li C, Kang NL, Malhi H, Shah VH & Maiers JL (2019) Transforming growth factor (TGF) cross-talk with the unfolded protein response is critical for hepatic stellate cell activation. J Biol Chem 294, 3137-3151.
de Galarreta MR, Navarro A, Ansorena E, Garzon AG, Modol T, Lopez-Zabalza MJ, Martinez-Irujo JJ, & Iraburu MJ (2016) Unfolded protein response induced by Brefeldin A increases collagen type I levels in hepatic stellate cells through an IRE1alpha, p38 MAPK and Smad-dependent pathway. Biochim Biophys Acta 1863, 2115-2123.
Hernandez-Gea V, Hilscher M, Rozenfeld R, Lim MP, Nieto N, Werner S, Devi LA & Friedman SL (2013) Endoplasmic reticulum stress induces fibrogenic activity in hepatic stellate cells through autophagy. J Hepatol 59, 98-104.
Kim RS, Hasegawa D, Goossens N, Tsuchida T, Athwal V, Sun XC, Robinson CL, Bhattacharya D, Chou H-I, Zhang DY et al. (2016) The XBP1 arm of the unfolded protein response induces fibrogenic activity in hepatic stellate cells through autophagy. Sci Rep 6, 39342.
Mannaerts I, Thoen LFR, Eysackers N, Cubero FJ, Leite SB, Coldham I, Colle I, Trautwein C & van Grunsven LA (2019) Unfolded protein response is an early, non-critical event during hepatic stellate cell activation. Cell Death Dis 10, 98.
Maiers JL, Kostallari E, Mushref M, deAssuncao TM, Li H, Jalan-Sakrikar N, Huebert RC, Cao S, Malhi H & Shah VH (2017) The unfolded protein response mediates fibrogenesis and collagen I secretion through regulating TANGO1 in mice. Hepatology 65, 983-998.
Zhu J, Wang R, Xu T, Zhang S, Zhao Y, Li Z, Wang C, Zhou J, Gao D, Hu Y et al. (2018) Salvianolic acid A attenuates endoplasmic reticulum stress and protects against cholestasis-induced liver fibrosis via the SIRT1/HSF1 pathway. Front Pharmacol 9, 1277.
De Minicis S, Candelaresi C, Agostinelli L, Taffetani S, Saccomanno S, Rychlicki C, Trozzi L, Marzioni M, Benedetti A & Svegliati-Baroni G (2012) Endoplasmic reticulum stress induces hepatic stellate cell apoptosis and contributes to fibrosis resolution. Liver Int 32, 1574-1584.
Borkham-Kamphorst E, Steffen BT, Van de Leur E, Haas U, Tihaa L, Friedman SL & Weiskirchen R (2016) CCN1/CYR61 overexpression in hepatic stellate cells induces ER stress-related apoptosis. Cell Signal 28, 34-42.
Lim MP, Devi LA & Rozenfeld R (2011) Cannabidiol causes activated hepatic stellate cell death through a mechanism of endoplasmic reticulum stress-induced apoptosis. Cell Death Dis 2, e170.
Huang Y, Li XH, Wang YR, Wang H, Huang C & Li J (2014) Endoplasmic reticulum stress-induced hepatic stellate cell apoptosis through calcium-mediated JNK/P38 MAPK and Calpain/Caspase-12 pathways. Mol Cell Biochem 394, 1-12.
Kawasaki K, Ushioda R, Ito S, Ikeda K, Masago Y & Nagata K (2015) Deletion of the collagen-specific molecular chaperone Hsp47 causes endoplasmic reticulum stress-mediated apoptosis of hepatic stellate cells. J Biol Chem 290, 3639-3646.
Zhu YJ, Men RT, Wen MY, Hu XL, Liu XJ & Yang L (2014) Blockage of TRPM7 channel induces hepatic stellate cell death through endoplasmic reticulum stress-mediated apoptosis. Life Sci 94, 37-44.
Wang C, Zhang F, Cao Y, Zhang M, Wang A, Xu M, Su M, Zhang M & Zhuge Y (2016) Etoposide induces apoptosis in activated human hepatic stellate cells via ER stress. Sci Rep 6, 34330.
Li Y, Chen Y, Huang H, Shi M, Yang W, Kuang J & Yan J (2017) Autophagy mediated by endoplasmic reticulum stress enhances the caffeine-induced apoptosis of hepatic stellate cells. Int J Mol Med 40, 1405-1414.
He L, Hou X, Fan F & Wu H (2016) Quercetin stimulates mitochondrial apoptosis dependent on activation of endoplasmic reticulum stress in hepatic stellate cells. Pharm Biol 54, 3237-3243.
Borkham-Kamphorst E, Steffen BT, van de Leur E, Haas U & Weiskirchen R (2018) Portal myofibroblasts are sensitive to CCN-mediated endoplasmic reticulum stress-related apoptosis with potential to attenuate biliary fibrogenesis. Cell Signal 51, 72-85.
Borkham-Kamphorst E, Steffen BT, Van de Leur E, Tihaa L, Haas U, Woitok MM, Meurer SK & Weiskirchen R (2016) Adenoviral CCN gene transfers induce in vitro and in vivo endoplasmic reticulum stress and unfolded protein response. Biochim Biophys Acta 1863, 2604-2612.
Wangensteen KJ & Chang KM (2020) Multiple roles for hepatitis B and C viruses and the host in the development of hepatocellular carcinoma. Hepatology 73(S1), 27-37.
Arzumanyan A, Reis HM & Feitelson MA (2013) Pathogenic mechanisms in HBV- and HCV-associated hepatocellular carcinoma. Nat Rev Cancer 13, 123-135.
Tardif KD, Mori K & Siddiqui A (2002) Hepatitis C virus subgenomic replicons induce endoplasmic reticulum stress activating an intracellular signaling pathway. J Virol 76, 7453-7459.
Tardif KD, Mori K, Kaufman RJ & Siddiqui A (2004) Hepatitis C virus suppresses the IRE1-XBP1 pathway of the unfolded protein response. J Biol Chem 279, 17158-17164.
Asselah T, Bieche I, Mansouri A, Laurendeau I, Cazals-Hatem D, Feldmann G, Bedossa P, Paradis V, Martinot-Peignoux M, Lebrec D et al. (2010) In vivo hepatic endoplasmic reticulum stress in patients with chronic hepatitis C. J Pathol 221, 264-274.
Verchot J (2016) How does the stressed out ER find relief during virus infection? Curr Opin Virol 17, 74-79.
Irshad M, Gupta P & Irshad K (2017) Molecular basis of hepatocellular carcinoma induced by hepatitis C virus infection. World J Hepatol 9, 1305-1314.
Li B, Gao B, Ye L, Han X, Wang W, Kong L, Fang X, Zeng Y, Zheng H, Li S et al. (2007) Hepatitis B virus X protein (HBx) activates ATF6 and IRE1-XBP1 pathways of unfolded protein response. Virus Res 124, 44-49.
Wang HC, Wu HC, Chen CF, Fausto N, Lei HY & Su IJ (2003) Different types of ground glass hepatocytes in chronic hepatitis B virus infection contain specific pre-S mutants that may induce endoplasmic reticulum stress. Am J Pathol 163, 2441-2449.
Hsieh YH (2004) Pre-S mutant surface antigens in chronic hepatitis B virus infection induce oxidative stress and DNA damage. Carcinogenesis 25, 2023-2032.
Obacz J, Avril T, Rubio-Patino C, Bossowski JP, Igbaria A, Ricci JE & Chevet E (2019) Regulation of tumor-stroma interactions by the unfolded protein response. FEBS J 286, 279-296.
Rodvold JJ, Mahadevan NR & Zanetti M (2016) Immune modulation by ER stress and inflammation in the tumor microenvironment. Cancer Lett 380, 227-236.
Dasgupta D, Nakao Y, Mauer AS, Thompson JM, Sehrawat TS, Liao CY, Krishnan A, Lucien F, Guo Q, Liu M et al. (2020) IRE1A stimulates hepatocyte-derived extracellular vesicles that promote inflammation in mice with steatohepatitis. Gastroenterology 159, 1487-1503.e17.
Liu J, Fan L, Yu H, Zhang J, He Y, Feng D, Wang F, Li X, Liu Q, Li Y et al. (2019) Endoplasmic reticulum stress causes liver cancer cells to release exosomal miR-23a-3p and up-regulate programmed death ligand 1 expression in macrophages. Hepatology 70, 241-258.
Soto-Pantoja DR, Wilson AS, Clear KY, Westwood B, Triozzi PL & Cook KL (2017) Unfolded protein response signaling impacts macrophage polarity to modulate breast cancer cell clearance and melanoma immune checkpoint therapy responsiveness. Oncotarget 8, 80545-80559.
Oh J, Riek AE, Weng SR, Petty M, Kim D, Colonna M, Cella M & Bernal-Mizrachi C (2012) Endoplasmic reticulum stress controls M2 macrophage differentiation and foam cell formation. J Biol Chem 287, 11629-11641.
Tan HY, Wang N, Tsao SW, Che CM, Yuen MF & Feng Y (2016) IRE1alpha inhibition by natural compound genipin on tumour associated macrophages reduces growth of hepatocellular carcinoma. Oncotarget 7, 43792-43804.
Pavlovic N, Kopsida M, Gerwins P & Heindryckx F (2020) Inhibiting P2Y12 in macrophages induces endoplasmic reticulum stress and promotes an anti-tumoral phenotype. Int J Mol Sci 21, 8177.
Yang FJ, Liu Y, Ren HZ, Zhou G, Yuan XW & Shi XL (2019) ER-stress regulates macrophage polarization through pancreatic EIF-2alpha kinase. Cell Immunol 336, 40-47.
Roos C, Westergren J, Dahlgren D, Lennernas H & Sjogren E (2018) Mechanistic modelling of intestinal drug absorption - the in vivo effects of nanoparticles, hydrodynamics, and colloidal structures. Eur J Pharm Biopharm 133, 70-76.
Effect of endoplasmic reticulum stress on metabolic function. US Clinical Trials Registry.
Ghobrial IM, Vij R, Siegel D, Badros A, Kaufman J, Raje N, Jakubowiak A, Savona MR, Obreja M & Berdeja JG (2019) A phase Ib/II study of oprozomib in patients with advanced multiple myeloma and waldenstrom macroglobulinemia. Clin Cancer Res 25, 4907-4916.
Wu X, Tang P, Li S, Wang S, Liang Y, Zhong L, Ren L, Zhang T & Zhang Y (2018) A randomized and open-label phase II trial reports the efficacy of neoadjuvant lobaplatin in breast cancer. Nat Commun 9, 832.
Vogl DT, Martin TG, Vij R, Hari P, Mikhael JR, Siegel D, Wu KL, Delforge M & Gasparetto C (2017) Phase I/II study of the novel proteasome inhibitor delanzomib (CEP-18770) for relapsed and refractory multiple myeloma. Leuk Lymphoma 58, 1872-1879.
Riche DM, McEwen CL, Riche KD, Sherman JJ, Wofford MR, Deschamp D & Griswold M (2013) Analysis of safety from a human clinical trial with pterostilbene. J Toxicol 2013, 463595.