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2.
Molecules ; 26(15)2021 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-34361578

RESUMO

Nitroreductase as a potential biomarker for aggressive tumors has received extensive attention. In this work, a novel NIR fluorescent probe for nitroreductase detection was synthesized. The probe Py-SiRh-NTR displayed excellent sensitivity and selectivity. Most importantly, the confocal fluorescence imaging demonstrated that HepG-2 cells treated with Py-SiRh-NTR under hypoxic conditions showed obvious enhanced fluorescence, which means that the NTR was overexpressed under hypoxic conditions. Moreover, the probe showed great promise that could help us to study related anticancer mechanisms research.


Assuntos
Corantes Fluorescentes , Proteínas de Neoplasias/metabolismo , Neoplasias , Nitrorredutases/metabolismo , Hipóxia Celular , Corantes Fluorescentes/química , Corantes Fluorescentes/farmacocinética , Corantes Fluorescentes/farmacologia , Células Hep G2 , Humanos , Microscopia de Fluorescência , Neoplasias/diagnóstico por imagem , Neoplasias/enzimologia
3.
Int J Mol Sci ; 22(16)2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34445633

RESUMO

Caspases, a family of cysteine-aspartic proteases, have an established role as critical components in the activation and initiation of apoptosis. Alongside this a variety of non-apoptotic caspase functions in proliferation, differentiation, cellular plasticity and cell migration have been reported. The activity level and context are important factors in determining caspase function. As a consequence of their critical role in apoptosis and beyond, caspases are uniquely situated to have pathological roles, including in cancer. Altered caspase function is a common trait in a variety of cancers, with apoptotic evasion defined as a "hallmark of cancer". However, the role that caspases play in cancer is much more complex, acting both to prevent and to promote tumourigenesis. This review focuses on the major findings in Drosophila on the dual role of caspases in tumourigenesis. This has major implications for cancer treatments, including chemotherapy and radiotherapy, with the activation of apoptosis being the end goal. However, such treatments may inadvertently have adverse effects on promoting tumour progression and acerbating the cancer. A comprehensive understanding of the dual role of caspases will aid in the development of successful cancer therapeutic approaches.


Assuntos
Apoptose , Carcinogênese , Caspases/metabolismo , Neoplasias/patologia , Animais , Drosophila , Humanos , Neoplasias/enzimologia , Neoplasias/etiologia , Neoplasias/prevenção & controle
4.
Nat Commun ; 12(1): 5147, 2021 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-34446716

RESUMO

PTEN is frequently mutated in human cancers and PTEN mutants promote tumor progression and metastasis. PTEN mutations have been implicated in immune regulation, however, the underlying mechanism is largely unknown. Here, we report that PTENα, the isoform of PTEN, remains active in cancer bearing stop-gained PTEN mutations. Through counteraction of CD8+ T cell-mediated cytotoxicity, PTENα leads to T cell dysfunction and accelerates immune-resistant cancer progression. Clinical analysis further uncovers that PTENα-active mutations suppress host immune responses and result in poor prognosis in cancer as relative to PTENα-inactive mutations. Furthermore, germline deletion of Ptenα in mice increases cell susceptibility to immune attack through augmenting stress granule formation and limiting synthesis of peroxidases, leading to massive oxidative cell death and severe inflammatory damage. We propose that PTENα protects tumor from T cell killing and thus PTENα is a potential target in antitumor immunotherapy.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Neoplasias/enzimologia , Neoplasias/imunologia , PTEN Fosfo-Hidrolase/imunologia , Animais , Linfócitos T CD8-Positivos/enzimologia , Feminino , Humanos , Imunossupressão , Isoenzimas/genética , Isoenzimas/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação , Neoplasias/genética , PTEN Fosfo-Hidrolase/genética , Evasão Tumoral
5.
J Clin Pathol ; 74(10): 615-619, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34353877

RESUMO

Fumarate hydratase (FH), encoded by the FH gene, is an enzyme which catalyses the conversion of fumarate to L-malate as part of the tricarboxylic acid cycle. Biallelic germline mutations in FH result in fumaric aciduria, a metabolic disorder resulting in severe neurological and developmental abnormalities. Heterozygous germline mutations in FH result in hereditary leiomyomatosis and renal cell carcinoma, a cancer predisposition syndrome. FH deficiency has multiple oncogenic mechanisms including through promotion of aerobic glycolysis, induction of pseudohypoxia, post-translational protein modification and impairment of DNA damage repair by homologous recombination. FH-deficient neoplasms can present with characteristic morphological features that raise suspicion for FH alterations and also frequently demonstrate loss of FH immunoreactivity and intracellular accumulation of 2-succinocysteine, also detected by immunohistochemistry.


Assuntos
Fumarato Hidratase/deficiência , Fumarato Hidratase/metabolismo , Erros Inatos do Metabolismo/enzimologia , Hipotonia Muscular/enzimologia , Neoplasias/enzimologia , Transtornos Psicomotores/enzimologia , Animais , Fumarato Hidratase/genética , Regulação Enzimológica da Expressão Gênica , Predisposição Genética para Doença , Humanos , Leiomiomatose/enzimologia , Leiomiomatose/genética , Leiomiomatose/patologia , Erros Inatos do Metabolismo/genética , Hipotonia Muscular/genética , Mutação , Neoplasias/genética , Neoplasias/patologia , Síndromes Neoplásicas Hereditárias/enzimologia , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/patologia , Fenótipo , Transtornos Psicomotores/genética , Neoplasias Cutâneas/enzimologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Neoplasias Uterinas/enzimologia , Neoplasias Uterinas/genética , Neoplasias Uterinas/patologia
6.
FEBS Lett ; 595(16): 2071-2084, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34245011

RESUMO

Human coilin-interacting nuclear ATPase protein (hCINAP), also known as adenylate kinase 6 (AK6), is an atypical adenylate kinase with critical roles in many biological processes, including gene transcription, ribosome synthesis, cell metabolism, cell proliferation and apoptosis, DNA damage responses, and genome stability. Furthermore, hCINAP/AK6 dysfunction is associated with cancer and various inflammatory diseases. In this review, we summarize the structural features and biological roles of hCINAP in several important signaling pathways, as well as its connection with tumor onset and progression.


Assuntos
Carcinogênese , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/metabolismo , Progressão da Doença , Neoplasias/enzimologia , Neoplasias/patologia , Humanos
7.
Nat Commun ; 12(1): 4045, 2021 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-34193876

RESUMO

RAS mutations are the most common oncogenic drivers across human cancers, but there remains a paucity of clinically-validated pharmacological inhibitors of RAS, as druggable pockets have proven difficult to identify. Here, we identify two RAS-binding Affimer proteins, K3 and K6, that inhibit nucleotide exchange and downstream signaling pathways with distinct isoform and mutant profiles. Affimer K6 binds in the SI/SII pocket, whilst Affimer K3 is a non-covalent inhibitor of the SII region that reveals a conformer of wild-type RAS with a large, druggable SII/α3 pocket. Competitive NanoBRET between the RAS-binding Affimers and known RAS binding small-molecules demonstrates the potential to use Affimers as tools to identify pharmacophores. This work highlights the potential of using biologics with small interface surfaces to select unseen, druggable conformations in conjunction with pharmacophore identification for hard-to-drug proteins.


Assuntos
Produtos Biológicos/farmacologia , Técnicas de Visualização da Superfície Celular/métodos , Descoberta de Drogas/métodos , Neoplasias/tratamento farmacológico , Proteínas ras/antagonistas & inibidores , Sítio Alostérico , Produtos Biológicos/química , Humanos , Neoplasias/química , Neoplasias/enzimologia , Transdução de Sinais , Proteínas ras/metabolismo
9.
Int J Mol Sci ; 22(12)2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-34207520

RESUMO

The 26S proteasome is the principal protease for regulated intracellular proteolysis. This multi-subunit complex is also pivotal for clearance of harmful proteins that are produced throughout the lifetime of eukaryotes. Recent structural and kinetic studies have revealed a multitude of conformational states of the proteasome in substrate-free and substrate-engaged forms. These conformational transitions demonstrate that proteasome is a highly dynamic machinery during substrate processing that can be also controlled by a number of proteasome-associated factors. Essentially, three distinct family of deubiquitinases-USP14, RPN11, and UCH37-are associated with the 19S regulatory particle of human proteasome. USP14 and UCH37 are capable of editing ubiquitin conjugates during the process of their dynamic engagement into the proteasome prior to the catalytic commitment. In contrast, RPN11-mediated deubiquitination is directly coupled to substrate degradation by sensing the proteasome's conformational switch into the commitment steps. Therefore, proteasome-bound deubiquitinases are likely to tailor the degradation events in accordance with substrate processing steps and for dynamic proteolysis outcomes. Recent chemical screening efforts have yielded highly selective small-molecule inhibitors for targeting proteasomal deubiquitinases, such as USP14 and RPN11. USP14 inhibitors, IU1 and its progeny, were found to promote the degradation of a subset of substrates probably by overriding USP14-imposed checkpoint on the proteasome. On the other hand, capzimin, a RPN11 inhibitor, stabilized the proteasome substrates and showed the anti-proliferative effects on cancer cells. It is highly conceivable that these specific inhibitors will aid to dissect the role of each deubiquitinase on the proteasome. Moreover, customized targeting of proteasome-associated deubiquitinases may also provide versatile therapeutic strategies for induced or repressed protein degradation depending on proteolytic demand and cellular context.


Assuntos
Inibidores Enzimáticos , Proteínas de Neoplasias , Neoplasias , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise/efeitos dos fármacos , Pirróis , Pirrolidinas , Ubiquitina Tiolesterase , Inibidores Enzimáticos/química , Inibidores Enzimáticos/uso terapêutico , Humanos , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Neoplasias/patologia , Pirróis/química , Pirróis/uso terapêutico , Pirrolidinas/química , Pirrolidinas/uso terapêutico , Ubiquitina Tiolesterase/antagonistas & inibidores , Ubiquitina Tiolesterase/metabolismo
10.
Nat Commun ; 12(1): 4055, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34210965

RESUMO

Poly(ADP-ribose) polymerase 1 (PARP1) and PARP2 are recruited and activated by DNA damage, resulting in ADP-ribosylation at numerous sites, both within PARP1 itself and in other proteins. Several PARP1 and PARP2 inhibitors are currently employed in the clinic or undergoing trials for treatment of various cancers. These drugs act primarily by trapping PARP1 on damaged chromatin, which can lead to cell death, especially in cells with DNA repair defects. Although PARP1 trapping is thought to be caused primarily by the catalytic inhibition of PARP-dependent modification, implying that ADP-ribosylation (ADPr) can counteract trapping, it is not known which exact sites are important for this process. Following recent findings that PARP1- or PARP2-mediated modification is predominantly serine-linked, we demonstrate here that serine ADPr plays a vital role in cellular responses to PARP1/PARP2 inhibitors. Specifically, we identify three serine residues within PARP1 (499, 507, and 519) as key sites whose efficient HPF1-dependent modification counters PARP1 trapping and contributes to inhibitor tolerance. Our data implicate genes that encode serine-specific ADPr regulators, HPF1 and ARH3, as potential PARP1/PARP2 inhibitor therapy biomarkers.


Assuntos
Proteínas de Transporte/metabolismo , Dano ao DNA , Reparo do DNA , Neoplasias/tratamento farmacológico , Proteínas Nucleares/metabolismo , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Serina/metabolismo , ADP-Ribosilação , Linhagem Celular , Linhagem Celular Tumoral , Humanos , Neoplasias/enzimologia , Poli(ADP-Ribose) Polimerase-1/metabolismo , Poli(ADP-Ribose) Polimerases/química , Poli(ADP-Ribose) Polimerases/metabolismo , Processamento de Proteína Pós-Traducional
11.
Int J Biol Sci ; 17(9): 2348-2355, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34239361

RESUMO

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has led to more than 150 million infections and about 3.1 million deaths up to date. Currently, drugs screened are urgently aiming to block the infection of SARS-CoV-2. Here, we explored the interaction networks of kinase and COVID-19 crosstalk, and identified phosphoinositide 3-kinase (PI3K)/AKT pathway as the most important kinase signal pathway involving COVID-19. Further, we found a PI3K/AKT signal pathway inhibitor capivasertib restricted the entry of SARS-CoV-2 into cells under non-cytotoxic concentrations. Lastly, the signal axis PI3K/AKT/FYVE finger-containing phosphoinositide kinase (PIKfyve)/PtdIns(3,5)P2 was revealed to play a key role during the cellular entry of viruses including SARS-CoV-2, possibly providing potential antiviral targets. Altogether, our study suggests that the PI3K/AKT kinase inhibitor drugs may be a promising anti-SARS-CoV-2 strategy for clinical application, especially for managing cancer patients with COVID-19 in the pandemic era.


Assuntos
COVID-19/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , SARS-CoV-2/efeitos dos fármacos , Internalização do Vírus/efeitos dos fármacos , Animais , COVID-19/enzimologia , Chlorocebus aethiops , Simulação por Computador , Humanos , Neoplasias/enzimologia , Neoplasias/mortalidade , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirimidinas/farmacologia , Pirróis/farmacologia , Receptor Cross-Talk , Células Vero
12.
Int J Mol Sci ; 22(14)2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34299213

RESUMO

The MEK5/ERK5 mitogen-activated protein kinases (MAPK) cascade is a unique signaling module activated by both mitogens and stress stimuli, including cytokines, fluid shear stress, high osmolarity, and oxidative stress. Physiologically, it is mainly known as a mechanoreceptive pathway in the endothelium, where it transduces the various vasoprotective effects of laminar blood flow. However, it also maintains integrity in other tissues exposed to mechanical stress, including bone, cartilage, and muscle, where it exerts a key function as a survival and differentiation pathway. Beyond its diverse physiological roles, the MEK5/ERK5 pathway has also been implicated in various diseases, including cancer, where it has recently emerged as a major escape route, sustaining tumor cell survival and proliferation under drug stress. In addition, MEK5/ERK5 dysfunction may foster cardiovascular diseases such as atherosclerosis. Here, we highlight the importance of the MEK5/ERK5 pathway in health and disease, focusing on its role as a protective cascade in mechanical stress-exposed healthy tissues and its function as a therapy resistance pathway in cancers. We discuss the perspective of targeting this cascade for cancer treatment and weigh its chances and potential risks when considering its emerging role as a protective stress response pathway.


Assuntos
Aterosclerose/fisiopatologia , MAP Quinase Quinase 5/metabolismo , Sistema de Sinalização das MAP Quinases , Proteína Quinase 7 Ativada por Mitógeno/metabolismo , Animais , Aterosclerose/metabolismo , Humanos , Neoplasias/enzimologia , Neoplasias/metabolismo
13.
Nucleic Acids Res ; 49(13): 7492-7506, 2021 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-34197599

RESUMO

Tumor heterogeneity includes variable and fluctuating oxygen concentrations, which result in the accumulation of hypoxic regions in most solid tumors. Tumor hypoxia leads to increased therapy resistance and has been linked to genomic instability. Here, we tested the hypothesis that exposure to levels of hypoxia that cause replication stress could increase APOBEC activity and the accumulation of APOBEC-mediated mutations. APOBEC-dependent mutational signatures have been well-characterized, although the physiological conditions which underpin them have not been described. We demonstrate that fluctuating/cyclic hypoxic conditions which lead to replication catastrophe induce the expression and activity of APOBEC3B. In contrast, stable/chronic hypoxic conditions which induce replication stress in the absence of DNA damage are not sufficient to induce APOBEC3B. Most importantly, the number of APOBEC-mediated mutations in patient tumors correlated with a hypoxia signature. Together, our data support the conclusion that hypoxia-induced replication catastrophe drives genomic instability in tumors, specifically through increasing the activity of APOBEC3B.


Assuntos
Citidina Desaminase/metabolismo , Replicação do DNA , Antígenos de Histocompatibilidade Menor/metabolismo , Neoplasias/enzimologia , Desaminases APOBEC/metabolismo , Hipóxia Celular , Linhagem Celular Tumoral , Desaminação , Humanos , Hidroxiureia/toxicidade , Estresse Fisiológico/genética
14.
Int J Biol Macromol ; 183: 2364-2375, 2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-34111484

RESUMO

TANK-binding kinase 1 (TBK1) regulates various biological processes including, NF-κB signaling, immune response, autophagy, cell division, Ras-mediated oncogenesis, and AKT pro-survival signaling. Enhanced TBK1 activity is associated with autoimmune diseases and cancer, suggesting its role in therapeutic targeting of interferonopathies. In addition, dysregulation of TBK1 activity promotes several inflammatory disorders and oncogenesis. Structural and biochemical study reports provide the molecular process of TBK1 activation and recap the substrate selection about TBK1. This review summarizes recent findings on the molecular mechanisms by which TBK1 is involved in cancer signaling. The IKK-ε and TBK1 are together associated with inflammatory diseases by inducing type I IFNs. Furthermore, TBK1 signaling regulates radiation-induced epithelial-mesenchymal transition by controlling phosphorylation of GSK-3ß and expression of Zinc finger E-box-binding homeobox 1, suggesting, TBK1 could be targeted for radiotherapy-induced metastasis therapy. Despite a considerable increase in the list of TBK1 inhibitors, only a few has potential to control cancer. Among them, a compound BX795 is considered a potent and selective inhibitor of TBK1. We discussed the therapeutic potential of small-molecule inhibitors of TBK1, particularly those with high selectivity, which will enable further exploration in the therapeutic management of cancer and inflammatory diseases.


Assuntos
Neoplasias/enzimologia , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Animais , Antineoplásicos/farmacologia , Autofagia , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , Mediadores da Inflamação/metabolismo , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Neoplasias/patologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Transdução de Sinais/efeitos dos fármacos , Microambiente Tumoral
16.
J Phys Chem Lett ; 12(26): 6095-6101, 2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34170697

RESUMO

Human isocitrate dehydrogenase (IDH1) and its cancer-associated variant (IDH1 R132H) are rendered electroactive through coconfinement with a rapid NADP(H) recycling enzyme (ferredoxin-NADP+ reductase) in nanopores formed within an indium tin oxide electrode. Efficient coupling to localized NADP(H) enables IDH activity to be energized, controlled, and monitored in real time, leading directly to a thermodynamic redox landscape for accumulation of the oncometabolite, 2-hydroxyglutarate, that would occur in biological environments when the R132H variant is present. The technique enables time-resolved, in situ measurements of the kinetics of binding and dissociation of inhibitory drugs.


Assuntos
Enzimas , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/metabolismo , Mutação , Nanotecnologia/instrumentação , Neoplasias/genética , Eletrodos , Humanos , Cinética , Neoplasias/enzimologia , Oxirredução , Termodinâmica
17.
J Biomed Sci ; 28(1): 41, 2021 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-34082769

RESUMO

Lysine-specific demethylase 1 (LSD1) targets mono- or di-methylated histone H3K4 and H3K9 as well as non-histone substrates and functions in the regulation of gene expression as a transcriptional repressor or activator. This enzyme plays a pivotal role in various physiological processes, including development, differentiation, inflammation, thermogenesis, neuronal and cerebral physiology, and the maintenance of stemness in stem cells. LSD1 also participates in pathological processes, including cancer as the most representative disease. It promotes oncogenesis by facilitating the survival of cancer cells and by generating a pro-cancer microenvironment. In this review, we discuss the role of LSD1 in several aspects of cancer, such as hypoxia, epithelial-to-mesenchymal transition, stemness versus differentiation of cancer stem cells, as well as anti-tumor immunity. Additionally, the current understanding of the involvement of LSD1 in various other pathological processes is discussed.


Assuntos
Histona Desmetilases/genética , Homeostase/genética , Neoplasias/genética , Animais , Diferenciação Celular/genética , Transição Epitelial-Mesenquimal/genética , Histona Desmetilases/imunologia , Histona Desmetilases/metabolismo , Homeostase/imunologia , Humanos , Hipóxia/enzimologia , Hipóxia/genética , Hipóxia/imunologia , Camundongos , Neoplasias/enzimologia , Neoplasias/imunologia , Células-Tronco Neoplásicas/fisiologia , Evasão Tumoral/genética
18.
Biochim Biophys Acta Rev Cancer ; 1876(1): 188578, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34116173

RESUMO

In cancer cells, tumor suppressor proteins loss-of-function are usually the result of genetic mutations. Protein Phosphatase 2A is a tumor suppressor that inactivates several signaling pathways through removal of phosphate residues important for other proteins stability and/or activation. Different from other tumor suppressors, PP2A is, in many cancer types, inactivated by endogenous inhibitors. In physiological conditions, these inhibitors are important to balance PP2A activity. However, in cancer cells, overexpression of these inhibitors can keep PP2A inactive, resulting in sustained activation of mitogenic signaling pathways and transcription factors, metabolic reprogramming, with the resulting cancer progression and the resistance to anti-cancer therapies. One of these endogenous inhibitors is the protein SET (SE Translocation). SET is a multifunctional protein, which high expression has been associated with several types of cancer, as well as other diseases such as Alzheimer's disease. Disruption of the interaction between SET and PP2A to rescue the activity of PP2A may represent a new therapeutic strategy and opportunity for cancer treatment. This review brings up-to-date advances on the interactions between SET and PP2A and their biological consequences. Moreover, we review reported inhibitors of SET-PP2A interaction under investigation as therapeutic opportunities for the treatment of cancers.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Chaperonas de Histonas/metabolismo , Neoplasias/enzimologia , Proteína Fosfatase 2/metabolismo , Animais , Antineoplásicos/uso terapêutico , Proteínas de Ligação a DNA/genética , Resistencia a Medicamentos Antineoplásicos , Ativação Enzimática , Regulação Neoplásica da Expressão Gênica , Chaperonas de Histonas/genética , Humanos , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , Ligação Proteica , Proteína Fosfatase 2/genética , Transdução de Sinais
19.
Biochim Biophys Acta Rev Cancer ; 1876(1): 188581, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34144130

RESUMO

Proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a novel pharmacological target for hypercholesterolemia and associated cardiovascular diseases owing to its function to mediate the degradation of low-density lipoprotein receptor (LDLR). Findings over the past two decades have identified novel binding partners and cellular functions of PCSK9. Notably, PCSK9 is aberrantly expressed in a broad spectrum of cancers and apparently contributes to disease prognosis, indicating that PCSK9 could be a valuable cancer biomarker. Experimental studies demonstrate the contribution of PCSK9 in various aspects of cancer, including cell proliferation, apoptosis, invasion, metastasis, anti-tumor immunity and radioresistance, strengthening the idea that PCSK9 could be a promising therapeutic target. Here, we comprehensively review the involvement of PCSK9 in cancer, summarizing its aberrant expression, association with disease prognosis, biological functions and underlying mechanisms in various malignancies. Besides, we highlight the potential of PCSK9 as a future therapeutic target in personalized cancer medicine.


Assuntos
Neoplasias/enzimologia , Pró-Proteína Convertase 9/metabolismo , Animais , Antineoplásicos/uso terapêutico , Apoptose , Movimento Celular , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , Terapia de Alvo Molecular , Invasividade Neoplásica , Metástase Neoplásica , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , Pró-Proteína Convertase 9/antagonistas & inibidores , Pró-Proteína Convertase 9/genética , Inibidores de Serino Proteinase/uso terapêutico , Transdução de Sinais
20.
Biomolecules ; 11(6)2021 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-34067242

RESUMO

Oximes have been studied for decades because of their significant roles as acetylcholinesterase reactivators. Over the last twenty years, a large number of oximes have been reported with useful pharmaceutical properties, including compounds with antibacterial, anticancer, anti-arthritis, and anti-stroke activities. Many oximes are kinase inhibitors and have been shown to inhibit over 40 different kinases, including AMP-activated protein kinase (AMPK), phosphatidylinositol 3-kinase (PI3K), cyclin-dependent kinase (CDK), serine/threonine kinases glycogen synthase kinase 3 α/ß (GSK-3α/ß), Aurora A, B-Raf, Chk1, death-associated protein-kinase-related 2 (DRAK2), phosphorylase kinase (PhK), serum and glucocorticoid-regulated kinase (SGK), Janus tyrosine kinase (JAK), and multiple receptor and non-receptor tyrosine kinases. Some oximes are inhibitors of lipoxygenase 5, human neutrophil elastase, and proteinase 3. The oxime group contains two H-bond acceptors (nitrogen and oxygen atoms) and one H-bond donor (OH group), versus only one H-bond acceptor present in carbonyl groups. This feature, together with the high polarity of oxime groups, may lead to a significantly different mode of interaction with receptor binding sites compared to corresponding carbonyl compounds, despite small changes in the total size and shape of the compound. In addition, oximes can generate nitric oxide. This review is focused on oximes as kinase inhibitors with anticancer and anti-inflammatory activities. Oximes with non-kinase targets or mechanisms of anti-inflammatory activity are also discussed.


Assuntos
Anti-Inflamatórios , Antineoplásicos , Inibidores Enzimáticos , Neoplasias/tratamento farmacológico , Oximas , Anti-Inflamatórios/química , Anti-Inflamatórios/uso terapêutico , Antineoplásicos/química , Antineoplásicos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/uso terapêutico , Humanos , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/uso terapêutico , Neoplasias/enzimologia , Oximas/química , Oximas/uso terapêutico , Fosfotransferases/antagonistas & inibidores , Fosfotransferases/metabolismo
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