IRE1α-XBP1s pathway promotes prostate cancer by activating c-MYC signaling DOI Creative Commons
Xia Sheng, Hatice Zeynep Nenseth, Su Qu

et al.

Nature Communications, Journal Year: 2019, Volume and Issue: 10(1)

Published: Jan. 24, 2019

Abstract Activation of endoplasmic reticulum (ER) stress/the unfolded protein response (UPR) has been linked to cancer, but the molecular mechanisms are poorly understood and there is a paucity reagents translate this for cancer therapy. Here, we report that an IRE1α RNase-specific inhibitor, MKC8866, strongly inhibits prostate (PCa) tumor growth as monotherapy in multiple preclinical models mice shows synergistic antitumor effects with current PCa drugs. Interestingly, global transcriptomic analysis reveal IRE1α-XBP1s pathway activity required c-MYC signaling, one most highly activated oncogenic pathways PCa. XBP1s necessary optimal mRNA expression, establishing, first time, direct link between UPR oncogene activation. In addition, XBP1-specific gene expression signature associated prognosis. Our data establish signaling central indicate its targeting may offer novel treatment strategies.

Language: Английский

DNA-Encoded Chemical Libraries: A Comprehensive Review with Succesful Stories and Future Challenges DOI
Adrián Gironda-Martínez, Etienne J. Donckèle, Florent Samain

et al.

ACS Pharmacology & Translational Science, Journal Year: 2021, Volume and Issue: 4(4), P. 1265 - 1279

Published: June 14, 2021

DNA-encoded chemical libraries (DELs) represent a versatile and powerful technology platform for the discovery of small-molecule ligands to protein targets biological pharmaceutical interest. DELs are collections molecules, individually coupled distinctive DNA tags serving as amplifiable identification barcodes. Thanks advances in DNA-compatible reactions, selection methodologies, next-generation sequencing, data analysis, DEL allows construction screening unprecedented size, which has led highly potent ligands, some have progressed clinical trials. In this Review, we present an overview diverse approaches generation molecular repertoires. Recent success stories described, detailing how novel were isolated from campaigns further optimized by medicinal chemistry. The goal Review is capture most recent developments field, while also elaborating on future challenges improve therapeutic platform.

Language: Английский

Citations

206
Metabolic reprogramming toward oxidative phosphorylation identifies a therapeutic target for mantle cell lymphoma DOI Open Access
Liang Zhang, Yixin Yao, Shaojun Zhang

et al.

Science Translational Medicine, Journal Year: 2019, Volume and Issue: 11(491)

Published: May 8, 2019

Metabolic reprogramming is linked to cancer cell growth and proliferation, metastasis, therapeutic resistance in a multitude of cancers. Targeting dysregulated metabolic pathways overcome resistance, an urgent clinical need all relapsed/refractory cancers, remains difficult. Through genomic analyses specimens, we show that toward oxidative phosphorylation (OXPHOS) glutaminolysis associated with the Bruton's tyrosine kinase inhibitor ibrutinib mantle lymphoma (MCL), B subtype poor outcomes. Inhibition OXPHOS clinically applicable small molecule, IACS-010759, which targets complex I mitochondrial electron transport chain, results marked inhibition vitro vivo ibrutinib-resistant patient-derived models. This work suggests targeting subvert viable approach treat highly refractory malignancies.

Language: Английский

Citations

205
Peptide–nanoparticle conjugates: a next generation of diagnostic and therapeutic platforms? DOI Creative Commons
Woo‐Jin Jeong, Jiyoon Bu, Luke J. Kubiatowicz

et al.

Nano Convergence, Journal Year: 2018, Volume and Issue: 5(1)

Published: Dec. 1, 2018

Peptide–nanoparticle conjugates (PNCs) have recently emerged as a versatile tool for biomedical applications. Synergism between the two promising classes of materials allows enhanced control over their biological behaviors, overcoming intrinsic limitations individual materials. Over past decades, myriad PNCs has been developed various applications, such drug delivery, inhibition pathogenic biomolecular interactions, molecular imaging, and liquid biopsy. This paper provides comprehensive overview existing technologies that in broad field PNCs, offering guideline especially investigators who are new to this field.

Language: Английский

Citations

194
Targeting EMT in Cancer with Repurposed Metabolic Inhibitors DOI Creative Commons
Vignesh Ramesh, Thomas Brabletz, Paolo Ceppi

et al.

Trends in cancer, Journal Year: 2020, Volume and Issue: 6(11), P. 942 - 950

Published: July 15, 2020

Epithelial-to-mesenchymal transition (EMT), an embryonic phenotypic plasticity program, in cancer confers invasiveness, dissemination, and chemo/immunotherapy resistance.EMT drives through dynamic intermediate states (partial EMT), which possess high metastasis-initiating potential. Genomic functional analyses have determined the existence of EMT/partial EMT features multiple human types.EMT is associated with significant metabolic rewiring, some pathways promote maintain EMT.Repurposing antimetabolism drugs EMT-driven cancers could reduce incidence metastasis improve patients' response to treatments.A better understanding interdependence between metabolism accelerate discovery novel treatments for aggressive cancers. (EMT) determines most lethal cancer, formation chemoresistance, therefore represents attractive target oncology. However, direct targeting effector molecules is, cases, pharmacologically challenging. Since emerging research has highlighted distinct circuits involved EMT, we propose use metabolism-specific inhibitors, FDA approved or under clinical trials, as a drug repurposing approach cancer. Metabolism-inhibiting be coupled standard chemo- immunotherapy combat resistant classical developmental governed by switching epithelial phenotype cell mesenchymal form conferring various biological processes such gastrulation, neural crest migration, wound healing [1.Kalluri R. Weinberg R.A. The basics epithelial–mesenchymal transition.J. Clin. Invest. 2009; 119: 1420-1428Crossref PubMed Scopus (6986) Google Scholar]. Cancer being highly heterogeneous disease known its accumulations abnormalities cell, often recapitulates manipulates program partial transient fashion acquire advantageous survival propagation [2.Hanahan D. Hallmarks cancer: next generation.Cell. 2011; 144: 646-674Abstract Full Text PDF (39909) phenomenon mediated transcription factors, aiding enhanced invasive ability, dissemination distant sites, metastatic colonization, stemness, chemoresistance [3.Williams E.D. et al.Controversies around metastasis.Nat. Rev. Cancer. 2019; 19: 716-732Crossref (184) Scholar,4.Brabletz T. al.EMT cancer.Nat. 2018; 18: 128-134Crossref (973) In tissues, process also been observed fundamental early steps tumorigenesis [5.Sato M. al.Human lung cells progressed malignancy specific oncogenic manipulations.Mol. 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A. 116: 7353-7362Crossref (192) Dissemination tumor clusters collective migration proposed regulated EMT-dependent mechanisms [10.Lambert A.W. al.Emerging principles metastasis.Cell. 168: 670-691Abstract (1400) Several studies took logical quantitatively discern samples using gene expression-based signature metrics, identified correlation poor patient [11.Taube J.H. al.Core epithelial-to-mesenchymal interactome gene-expression claudin-low metaplastic subtypes.Proc. 2010; 107: 15449-15454Crossref (755) 12.Tan T.Z. al.Epithelial–mesenchymal spectrum quantification efficacy deciphering responses patients.EMBO Mol. Med. 2014; 6: 1279-1293Crossref (388) 13.George J.T. al.Survival outcomes patients predicted expression scoring metric.Cancer 77: 6415-6428Crossref (122) Importantly, pan-cancer derived across types revealed strong association immune checkpoint targets [14.Mak M.P. al.A patient-derived, identifies global molecular alterations enrichment following transition.Clin. 22: 609-620Crossref (260) Recently, including biopsies several advanced carcinomas [15.Navas al.Clinical evolution carcinomas.Cancer 2020; 80: 304-318PubMed These together unveil central role progression relevance. Moreover, contributes [16.Fischer K.R. al.Epithelial-to-mesenchymal not required but chemoresistance.Nature. 2015; 527: 472-476Crossref (1203) 17.Zheng X. dispensable induces pancreatic cancer.Nature. 525-530Crossref (1356) 18.Shibue CSCs, resistance: mechanistic link implications.Nat. Oncol. 611-629Crossref (1198) Scholar] resistance blockade [19.Horn L.A. al.Tumor immunotherapy.Trends 432-441Abstract (45) promotes chemotherapeutic cancers, cisplatin non-small (NSCLC) [20.Kurokawa al.Cisplatin influences acquisition molecular-targeted agents transition-like changes.Cancer 104: 904-911Crossref (40) gastric [21.Huang HER2 upregulation-induced transition.Sci. 20502Crossref (65) docetaxel prostate relapse [22.Marín-Aguilera mediates risk cancer.Mol. Ther. 13: 1270-1284Crossref (110) addition, occurrence chemoresistant (CSCs) bearing (CSC+/pEMT+) outcome was receiving chemotherapy [23.Papadaki M.A. al.Circulating stemness are predictive 437-447Crossref (84) All these observations indicate primary requisite development targeted treatment modalities suppressing combined overcome resistance. at level blocking key factors challenging [24.Dang C.V. al.Drugging 'undruggable' targets.Nat. 17: 502-508Crossref (377) We describe how inhibitory drugs, can EMT-associated processes. Cellular regulates biochemical indispensable internal external milieu [25.Mouchiroud L. al.Transcriptional coregulators: fine-tuning metabolism.Cell Metab. 20: 26-40Abstract (69) cells, particular fine-tune their circuitry meet increased bioenergetic demands encountering complex challenges cellular transit [26.Campbell S.L. Wellen K.E. Metabolic signaling nucleus 71: 398-408Abstract (80) Scholar,27.Halldorsson al.Metabolic re-wiring isogenic lines transition.Cancer Lett. 396: 117-129Crossref (37) Therefore, switch would unravel vulnerable therapeutic targets. reported reprogramming events EMT. Unsupervised clustering comprehensive collection mesenchyme-specific subgroup dihydropyrimidine (DHP) dehydrogenase (DPYD) enzyme-driven production DHPs [28.Shaul Y.D. al.Dihydropyrimidine accumulation transition.Cell. 158: 1094-1109Abstract (142) A further study compounds specifically mesenchyme-like largely inhibited glutathione peroxidase 4 (GPX4), lipid pathway evade ferroptosis, nonapoptotic death [29.Viswanathan V.S. al.Dependency therapy-resistant on pathway.Nature. 547: 453-457Crossref (624) rewiring overtly (EMT-TFs). For instance, ZEB1, transcriptional regulator, aids promoting glycosphingolipid [30.Mathow al.Zeb1 affects adhesion diverting metabolism.EMBO 16: 321-331Crossref (35) Similarly, SNAI1 repression fructose-1,6-bisphosphatase 1 (FBP1) activate glycolysis [31.Dong al.Loss FBP1 Snail-mediated provides advantages basal-like cancer.Cancer 23: 316-331Abstract (517) inevitable component cells. described upstream regulator plasticity. when TCA cycle enzyme fumarate hydratase (FH) ablated renal it causes turn epigenetically silences EMT-suppressing miRNA miR-200 [32.Ceppi P. Peter M.E. MicroRNAs regulate both cells.Oncogene. 33: 269-278Crossref (86) activates EMT-TFs [33.Sciacovelli al.Fumarate epigenetic modifier elicits transition.Nature. 537: 544-547Crossref (302) nucleotide thymidylate synthase (TS), typically involvement proliferation, shown de-differentiation DPYD-dependent pyrimidine catabolism [34.Siddiqui al.Thymidylate maintains de-differentiated triple negative cancers.Cell Death Differ. 26: 2223-2236Crossref (17) EMT-focused transcriptomic analysis elevated levels AKR1B1 contributing stemness. polyol pathway, two-step aldo-keto-reductase-1 B1 (AKR1B1) sorbitol (SORD), converts excess glucose fructose When activated glucose, induce autocrine TGF-β stimulation [35.Schwab al.Polyol links aggressiveness cells.Cancer 78: 1604-1618Crossref (49) Scholar], implicating connection D-2-Hydroxyglutarate, oncometabolite produced glutamine anaplerosis, induced ZEB1-mediated [36.Colvin H. al.Oncometabolite D-2-hydroxyglurate directly epithelial-mesenchymal colorectal cancer.Sci. 36289Crossref (67) branched-chain amino acid metabolism, counterpart α-keto kinase (BCKDK), [37.Tian Q. al.Phosphorylation BCKDK BCAA Y246 Src cancer.Oncogene. 39: 3980-3996Crossref (12) Collectively findings show interdependent and, priming exploitation level, effectively targeted. Here, discuss promising pharmacological inhibitors enzymes (summarized Table 1, Key Table), repurposed revert phenotypes.Table 1Key Table. List Metabolism-Inhibiting Drugs, Approved Under Clinical Trials, EMT-Inhibiting FeatureDrugTargetFDA approval/treatment forClinical trial forTrial IDSimvastatinHMG-CoAFDA hypolipidemiaAdvanced rectal cancerNCT02161822Pancreatic cancerNCT00944463Small cancerNCT01441349Brain metastasisNCT02104193OlaparibPARPFDA cancerMetastatic carcinomaNCT03786796DisulfiramALDH1FDA alcoholismMetastatic cancerNCT03323346CTC/EMT cancerNCT04265274EtodolacCOX-2FDA pain inflammationColorectal metastasisNCT03919461Metastatic cancerNCT03838029SuraminHeparanaseTreatment trypanosomiasisAutismNCT02508259Prostate cancerNCT00002881Advanced solid tumorsNCT00003038NSCLCNCT00066768RolipramPDE4Treatment depressionMultiple sclerosisNCT00011375L-NAMEiNOSCardiovascularNCT03684213CardiovascularNCT03679780L-NMMAMultiple cancersNCT03236935Metastatic TNBCNCT028344032-DGGlycolysisAdvanced tumorsNCT00096707AscorbateVitamin CResectable metastaticNCT03146962Pancreatic cancerNCT02905578Malignant tumorsNCT04033107 Open table new tab Below highlight importance repositioning FDA-approved under-trial inhibition mitigate (Figure 1). Given potential inclusion criterion EMT-guided selection trials additional benefit outcome. tabulated list (Table 1) demonstrates metabolism-centered represent valuable resource future Activation TGF-β, Wnt, Notch strongly [38.Thiery J.P. Sleeman Complex networks orchestrate transitions.Nat. Cell Biol. 2006; 7: 131-142Crossref (3152) rewire mediate process. increasing phosphodiesterase (PDE4), conversion cAMP AMP pool [39.Kolosionek al.Expression activity isoforms transition: 4.Mol. 4751-4765Crossref (77) Rolipram, selective inhibitor PDE4 anticancer antipsychotic effects [40.Goldhoff al.Targeted cyclic phosphodiesterase-4 brain regression.Clin. 2008; 7717-7725Crossref (103) Scholar,41.Wiescholleck V. Manahan-Vaughan enhances hippocampal synaptic vivo rescues MK801-induced impairment long-term potentiation object recognition memory animal model psychosis.Transl. Psychiatry. 2012; 2e89Crossref attenuated TGF-β-induced PDE4-mediated SMAD-independent manner reactive oxygen species (ROS) Pretreatment rolipram followed TGF-β1 showed increase markers (E-cadherin cytokeratin-18) decrease marker (fibronectin) transcript protein level. Interestingly, chemopreventive effect preventing [42.Yeo C.D. al.Chemopreventive phosphodieasterase-4 benzo(a)pyrene-induced murine model.Exp. Lung 40: 500-506Crossref (16) Similar rolipram, abrogated simvastatin, competitive 3-hydroxy-3-methylglutaryl-coenzyme (HMG-CoA) reductase used hyperlipidemia [43.Yang al.Simvastatin attenuates TGF-β1-induced alveolar cells.Cell. Physiol. 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Acta. 1843: 2122-2128Crossref (50) Selective heparanase suramin mitigated signet-ring (Slug, vimentin, α-SMA) along [48.Shah al.The close relationship adenocarcinoma.Oncotarget. 9: 33778-33787Crossref (11) Suramin widely African trypanosomiasis, randomized autism disorder [49.Naviaux R.K. al.Low-dose disorder: small, I/II, trial.Ann. Transl. Neurol. 4: 491-505Crossref I/II prior taxanes well-tolerated treated non-cytotoxic doses combination weekly paclitaxel [50.Lustberg M.B. al.Phase taxanes.Cancer Chemother. Pharmacol. 70: 49-56Crossref (22) Nitric oxide functions pro- antitumorigenic factor, nitric (NOS) L-arginine [51.Burke A.J. yin yang progression.Carcinogenesis. 34: 503-512Crossref (247) triple-negative (TNBC), endogenous inducible NOS (iNOS) potent iNOS-specific (1400W) pan-NOS (L-NAME L-NMMA) EMT-TFs, Snail, Slug, Twist, deregulated interconnected HIF-1α, ER stress, TGF-β/ATF3/ATF4 axis. tumor-initiating capacity CSCs [52.Granados-Principal al.Inhibition iNOS effective therapy against cancer.Breast 25Crossref (128) While clinically L-NMMA cause acute blood pressure elevation, administration amlodipine regimen orthotopic mouse models TNBC convincingly elevation L-NMMA. growth, docetaxel-treated group. accordance this, sensitivity patient-derived xenograft (PDX) [53.Dávila-González al.Pharmacological ASK1/JNK augmenting docetaxel-mediated apoptosis cancer.Clin. 24: 1152-1162Crossref test L-NAME treating cardiovascular diseases respectively Vitamin activity, ascorbate having selectivity towards normal [54.Ma al.High-dose parenteral chemosensitivity toxicity chemotherapy.Sci. 6222ra18Crossref (273) Intravenous potentially greater than oral counterpart, [55.Alexander M.S. al.Pharmacologic reduces radiation-induced tissue radiosensitization 6838-6851Crossref (47) 56.Allen B.G. al.First-in-human I pharmacologic radiation temozolomide newly diagnosed glioblastoma.Clin. 6590-6597Crossref (29) 57.Magrì vitamin C immunotherapy.Sci. 12eaay8707Crossref high-dose intravenous able inhibit agent gemcitabine mice xenografts. 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Inhibition ALDH1A1 overcame resistance-induced prolonged Acquisition ALDH1A1-induced dependent ROS (RCS) SOD2 GPX4, respectively, down

Language: Английский

Citations

194
IRE1α-XBP1s pathway promotes prostate cancer by activating c-MYC signaling DOI Creative Commons
Xia Sheng, Hatice Zeynep Nenseth, Su Qu

et al.

Nature Communications, Journal Year: 2019, Volume and Issue: 10(1)

Published: Jan. 24, 2019

Abstract Activation of endoplasmic reticulum (ER) stress/the unfolded protein response (UPR) has been linked to cancer, but the molecular mechanisms are poorly understood and there is a paucity reagents translate this for cancer therapy. Here, we report that an IRE1α RNase-specific inhibitor, MKC8866, strongly inhibits prostate (PCa) tumor growth as monotherapy in multiple preclinical models mice shows synergistic antitumor effects with current PCa drugs. Interestingly, global transcriptomic analysis reveal IRE1α-XBP1s pathway activity required c-MYC signaling, one most highly activated oncogenic pathways PCa. XBP1s necessary optimal mRNA expression, establishing, first time, direct link between UPR oncogene activation. In addition, XBP1-specific gene expression signature associated prognosis. Our data establish signaling central indicate its targeting may offer novel treatment strategies.

Language: Английский

Citations

187