Emerging applications of metabolomics in drug discovery and precision medicine

Nature Reviews Drug Discovery, Journal Year: 2016, Volume and Issue: 15(7), P. 473 - 484

Published: March 11, 2016

Language: Английский

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Endoplasmic Reticulum Stress and the Hallmarks of Cancer

Trends in cancer, Journal Year: 2016, Volume and Issue: 2(5), P. 252 - 262

Published: April 30, 2016

Language: Английский

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HSPA5 Regulates Ferroptotic Cell Death in Cancer Cells

Cancer Research, Journal Year: 2017, Volume and Issue: 77(8), P. 2064 - 2077

Published: Jan. 28, 2017

Abstract Ferroptosis is a form of regulated cell death driven by oxidative injury promoting lipid peroxidation, although detailed molecular regulators are largely unknown. Here, we show that heatshock 70-kDa protein 5 (HSPA5) negatively regulates ferroptosis in human pancreatic ductal adenocarcinoma (PDAC) cells. Mechanistically, activating transcription factor 4 (ATF4) resulted the induction HSPA5, which turn bound glutathione peroxidase (GPX4) and protected against GPX4 degradation subsequent peroxidation. Importantly, HSPA5–GPX4 pathway mediated resistance, limiting anticancer activity gemcitabine. Genetic or pharmacologic inhibition enhanced gemcitabine sensitivity disinhibiting vitro both subcutaneous orthotopic animal models PDAC. Collectively, these findings identify novel role HSPA5 suggest potential therapeutic strategy for overcoming resistance. Cancer Res; 77(8); 2064–77. ©2017 AACR.

Language: Английский

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Endocrine resistance in breast cancer – An overview and update

Molecular and Cellular Endocrinology, Journal Year: 2015, Volume and Issue: 418, P. 220 - 234

Published: Oct. 17, 2015

Language: Английский

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The epigenetic regulators and metabolic changes in ferroptosis-associated cancer progression

Molecular Cancer, Journal Year: 2020, Volume and Issue: 19(1)

Published: Feb. 27, 2020

Abstract Ferroptosis, a novel form of regulated cell death, is different from other types death in morphology, genetics and biochemistry. Increasing evidence indicates that ferroptosis has significant implications on linked to cardiomyopathy, tumorigenesis, cerebral hemorrhage name few. Here we summarize current literature ferroptosis, including organelle dysfunction, signaling transduction pathways, metabolic reprogramming epigenetic regulators cancer progression. With regard organelles, mitochondria-induced cysteine starvation, endoplasmic reticulum-related oxidative stress, lysosome dysfunction golgi stress-related lipid peroxidation all contribute induction ferroptosis. Understanding the underlying mechanism could provide insight into treatment various intractable diseases cancers.

Language: Английский

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Role of the unfolded protein response, GRP78 and GRP94 in organ homeostasis

Journal of Cellular Physiology, Journal Year: 2014, Volume and Issue: 230(7), P. 1413 - 1420

Published: Dec. 29, 2014

The endoplasmic reticulum (ER) is a cellular organelle where secretory and membrane proteins, as well lipids, are synthesized modified. When cells subjected to ER stress, an adaptive mechanism referred the Unfolded Protein Response (UPR) triggered allow restore homeostasis. Evidence has accumulated that UPR pathways provide specialized unique roles in diverse development metabolic processes. glucose regulated proteins (GRPs) traditionally regarded with chaperone calcium binding properties. GRPs constitutively expressed at basal levels all organs, stress-inducible chaperones, they major players protein folding, assembly degradation. This conventional concept augmented by recent discoveries can be actively translocated other locations such cell surface, assume novel functions regulate signaling, proliferation, apoptosis immunity. Recent construction characterization of mouse models gene encoding for components genetically altered new insights on physiological contribution these vivo. review highlights progress towards understanding role two (GRP78 GRP94) regulating homeostasis organs arising from endoderm, mesoderm ectoderm. GRP78 GRP94 exhibit shared functions, specific their depletion elicits responses consequences. J. Cell. Physiol. 230: 1413–1420, 2015. © 2014 Wiley Periodicals, Inc., A Company

Language: Английский

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Endoplasmic reticulum stress signaling and chemotherapy resistance in solid cancers

Oncogenesis, Journal Year: 2017, Volume and Issue: 6(8), P. e373 - e373

Published: Aug. 28, 2017

Abstract The unfolded protein response (UPR) is an adaptive cellular program used by eukaryotic cells to cope with misfolding stress. During tumor development, cancer are facing intrinsic (oncogene activation) and extrinsic (limiting nutrient or oxygen supply) challenges, which they must survive. Moreover, chemotherapy represents additional challenge that adapt in the case of resistance. As today, resistance targeted therapies one important issues oncologists have deal for treating patients. In this review, we first describe key molecular mechanisms controlling UPR their implication solid cancers. Then, review literature connects activation UPR. Finally, discuss possible applications targeting bypass drug

Language: Английский

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Maximizing the Therapeutic Potential of HSP90 Inhibitors

Molecular Cancer Research, Journal Year: 2015, Volume and Issue: 13(11), P. 1445 - 1451

Published: July 29, 2015

Abstract HSP90 is required for maintaining the stability and activity of a diverse group client proteins, including protein kinases, transcription factors, steroid hormone receptors involved in cell signaling, proliferation, survival, oncogenesis, cancer progression. Inhibition alters HSP90-client complex, leading to reduced activity, misfolding, ubiquitination, and, ultimately, proteasomal degradation proteins. inhibitors have demonstrated significant antitumor wide variety preclinical models, with evidence selectivity versus normal cells. In clinic, however, efficacy this class therapeutic agents has been relatively limited date, promising responses mainly observed breast lung cancer, but no major seen other tumor types. addition, adverse events some toxicities documented. Key improving these clinical outcomes better understanding cellular consequences inhibiting that may underlie treatment response or resistance. This review considers recent progress made study its highlights new opportunities maximize their potential. Mol Cancer Res; 13(11); 1445–51. ©2015 AACR.

Language: Английский

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Middle East respiratory syndrome coronavirus and bat coronavirus HKU9 both can utilize GRP78 for attachment onto host cells

Journal of Biological Chemistry, Journal Year: 2018, Volume and Issue: 293(30), P. 11709 - 11726

Published: June 10, 2018

Coronavirus tropism is predominantly determined by the interaction between coronavirus spikes and host receptors. In this regard, coronaviruses have evolved a complicated receptor-recognition system through their spike proteins. Spikes from highly related can recognize distinct receptors, whereas of distant employ same cell-surface molecule for entry. Moreover, broad range molecules in addition to receptors thereby augment attachment or The receptor Middle East respiratory syndrome (MERS-CoV) dipeptidyl peptidase 4 (DPP4). study, we identified membrane-associated 78-kDa glucose-regulated protein (GRP78) as an additional binding target MERS-CoV spike. Further analyses indicated that GRP78 could not independently render nonpermissive cells susceptible infection but facilitate entry into permissive augmenting virus attachment. More importantly, exploring potential interactions other coronaviruses, discovered conserved human interact with bat HKU9 (bCoV-HKU9) its cell surface. Taken together, our study has factor proteins two Betacoronaviruses, lineage C D bCoV-HKU9. capacity surface both phylogenetically exemplifies need continuous surveillance evolution animal monitor adaptations.

Language: Английский

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Ligand-targeted theranostic nanomedicines against cancer

Journal of Controlled Release, Journal Year: 2016, Volume and Issue: 240, P. 267 - 286

Published: Jan. 6, 2016

Nanomedicines have significant potential for cancer treatment. Although the majority of nanomedicines currently tested in clinical trials utilize simple, biocompatible liposome-based nanocarriers, their widespread use is limited by non-specificity and low target site concentration thus, do not provide a substantial advantage over conventional, systemic chemotherapy. In past 20 years, we identified specific receptors expressed on surfaces tumor endothelial perivascular cells, extracellular matrix stromal cells using combinatorial peptide libraries displayed bacteriophage. These studies corroborate notion that unique receptor proteins such as IL-11Rα, GRP78, EphA5, among others, are differentially overexpressed tumors present opportunities to deliver tumor-specific therapeutic drugs. By peptides bind cell-surface receptors, agents apoptotic peptides, suicide genes, imaging dyes or chemotherapeutics can be precisely systemically delivered reduce growth vivo, without harming healthy cells. Given applicability peptide-based therapeutics, targeted delivery nanocarriers loaded with cargos seems plausible. We propose modular design functionalized protocell which tumor-targeting moiety, recombinant human antibody single chain variable fragment (scFv), conjugated lipid bilayer surrounding silica-based nanocarrier core containing protected cargo. The tailored subtype treatment regimen exchanging moiety and/or cargo used combination create unique, theranostic agents. this review, summarize identification through phage display technology selection identify scFvs against these receptors. compare characteristics different types simple complex discuss conjugation strategies. protocells may improve efficacy safety future therapy.

Language: Английский

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