RESUMO
Metabolic reprogramming induced by Epstein-Barr virus (EBV) often mirrors metabolic changes observed in cancer cells. Accumulating evidence suggests that lytic reactivation is crucial in EBV-associated oncogenesis. The aim of this study was to explore the role of metabolite changes in EBV-associated malignancies and viral life cycle control. We first revealed that EBV (LMP1) accelerates the secretion of the oncometabolite D-2HG, and serum D-2HG level is a potential diagnostic biomarker for NPC. EBV (LMP1)-driven metabolite changes disrupts the homeostasis of global DNA methylation and demethylation, which have a significantly inhibitory effect on active DNA demethylation and 5hmC content. We found that loss of 5hmC indicates a poor prognosis for NPC patients, and that 5hmC modification is a restriction factor of EBV reactivation. We confirmed a novel EBV reactivation inhibitor, α-KG, which inhibits the expression of EBV lytic genes with CpG-containing ZREs and the latent-lytic switch by enhancing 5hmC modification. Our results demonstrate a novel mechanism of which metabolite abnormality driven by EBV controls the viral lytic reactivation through epigenetic modification. This study presents a potential strategy for blocking EBV reactivation, and provides potential targets for the diagnosis and therapy of NPC.
Assuntos
Metilação de DNA , Infecções por Vírus Epstein-Barr , Herpesvirus Humano 4 , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Ativação Viral , Humanos , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/fisiologia , Carcinoma Nasofaríngeo/virologia , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/virologia , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patologia , Infecções por Vírus Epstein-Barr/virologia , Infecções por Vírus Epstein-Barr/complicações , Proteínas da Matriz Viral/metabolismo , Proteínas da Matriz Viral/genética , Epigênese Genética , Progressão da DoençaRESUMO
Increasing evidence indicates that extracellular vesicles (EVs) play an important role in cancer cell-to-cell communication. The Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1), which is closely associated with nasopharyngeal carcinoma (NPC) pathogenesis, can trigger multiple cell signaling pathways that affect cell progression. Several reports have shown that LMP1 promotes EV secretion, and LMP1 trafficking by EVs can enhances cancer progression and metastasis. However, the molecular mechanism by which LMP1 promotes EV secretion is not well understood. In the present study, we found that LMP1 promotes EV secretion by upregulated syndecan-2 (SDC2) and synaptotagmin-like-4 (SYTL4) through nuclear factor (NF)-κB signaling in NPC cells. Further study indicated that SDC2 interacted with syntenin, which promoted the formation of the EVs, and SYTL4 is associated with the release of EVs. Moreover, we found that stimulation of EV secretion by LMP1 can enhance the proliferation and invasion ability of recipient NPC cells and tumor growth in vivo. In summary, we found a new mechanism by which LMP1 upregulates SDC2 and SYTL4 through NF-κB signaling to promote EV secretion, and further enhance cancer progression of NPC.
Assuntos
Vesículas Extracelulares/metabolismo , Herpesvirus Humano 4/metabolismo , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/metabolismo , Sindecana-2/metabolismo , Proteínas de Transporte Vesicular/metabolismo , Proteínas da Matriz Viral/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Feminino , Regulação Neoplásica da Expressão Gênica/fisiologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , NF-kappa B/metabolismo , Transdução de Sinais/fisiologia , Regulação para Cima/fisiologiaRESUMO
Deregulation of cellular metabolism is well established in cancer. The mitochondria are dynamic organelles and act as the center stage for energy metabolism. Central to mitochondrial regulatory network is peroxisome proliferator-activated receptor γ coactivator 1a (PGC-1α), which serves as a master regulator of mitochondrial proliferation and metabolism. The activity and stability of PGC-1α are subject to dynamic and versatile posttranslational modifications including phosphorylation, ubiquitination, methylation and acetylation in response to metabolic stress and other environmental signals. In this review, we describe the structure of PGC-1α. Then, we discuss recent advances in the posttranslational regulatory machinery of PGC-1α, which affects its transcriptional activity, stability and organelle localization. Furthermore, we address the important roles of PGC-1α in tumorigenesis and malignancy. Finally, we also mention the clinical therapeutic potentials of PGC-1α modulators. A better understanding of the elegant function of PGC-1α in cancer progression could provide novel insights into therapeutic interventions through the targeting of PGC-1α signaling.
Assuntos
Neoplasias/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Processamento de Proteína Pós-Traducional , Autofagia , Humanos , Metilação , Mitocôndrias/metabolismo , Mitofagia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/química , Fosforilação , Conformação Proteica , Transdução de SinaisRESUMO
The PPAR coactivator-1α (PGC1α) is an important transcriptional co-activator in control of fatty acid metabolism. Mitochondrial fatty acid oxidation (FAO) is the primary pathway for the degradation of fatty acids and promotes NADPH and ATP production. Our previous study demonstrated that upregulation of carnitine palmitoyl transferase 1 A (CPT1A), the key regulator of FAO, promotes radiation resistance of nasopharyngeal carcinoma (NPC). In this study, we found that high expression of PGC1α is associated with poor overall survival in NPC patients after radiation treatment. Targeting PGC1α could sensitize NPC cells to radiotherapy. Mechanically, PGC1α binds to CCAAT/enhancer binding protein ß (CEBPB), a member of the transcription factor family of CEBP, to promote CPT1A transcription, resulting in activation of FAO. Our results revealed that the PGC1α/CEBPB/CPT1A/FAO signaling axis promotes radiation resistance of NPC. These findings indicate that the expression of PGC1α could be a prognostic indicator of NPC, and targeting FAO in NPC with high expression of PGC1α might improve the therapeutic efficacy of radiotherapy.
Assuntos
Proteína beta Intensificadora de Ligação a CCAAT/genética , Carnitina O-Palmitoiltransferase/genética , Ácidos Graxos/metabolismo , Carcinoma Nasofaríngeo/radioterapia , Neoplasias Nasofaríngeas/radioterapia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Carnitina O-Palmitoiltransferase/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Humanos , Estimativa de Kaplan-Meier , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/metabolismo , Oxirredução/efeitos da radiação , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Regiões Promotoras Genéticas/genética , Ligação Proteica/efeitos da radiação , Interferência de RNARESUMO
In recent years, Epstein-Barr virus (EBV) lytic infection has been shown to significantly contribute to carcinogenesis. Thus, therapies aimed at targeting the EBV lytic cycle have been developed as novel strategies for treatment of EBV-associated malignancies. In this review, focusing on the viral lytic proteins, we describe recent advances regarding the involvement of the EBV lytic cycle in carcinogenesis. Moreover, we further discuss 2 distinct EBV lytic cycle-targeted therapeutic strategies against EBV-induced malignancies. One of the strategies involves inhibition of the EBV lytic cycle by natural compounds known to have anti-EBV properties; another is to intentionally induce EBV lytic replication in combination with nucleotide analogues. Recent advances in EBV lytic-based strategies are beginning to show promise in the treatment and/or prevention of EBV-related tumors.
Assuntos
Infecções por Vírus Epstein-Barr/complicações , Neoplasias/virologia , Replicação Viral , Herpesvirus Humano 4 , HumanosRESUMO
Cancer cells frequently display fundamentally altered cellular metabolism, which provides the biochemical foundation and directly contributes to tumorigenicity and malignancy. Rewiring of metabolic programmes, such as aerobic glycolysis and increased glutamine metabolism, are crucial for cancer cells to shed from a primary tumor, overcome the nutrient and energy deficit, and eventually survive and form metastases. However, the role of lipid metabolism that confers the aggressive properties of malignant cancers remains obscure. The present review is focused on key enzymes in lipid metabolism associated with metastatic disease pathogenesis. We also address the function of an important membrane structure-lipid raft in mediating tumor aggressive progression. We enumerate and integrate these recent findings into our current understanding of lipid metabolic reprogramming in cancer metastasis accompanied by new and exciting therapeutic implications.
Assuntos
Metabolismo dos Lipídeos , Neoplasias/metabolismo , Neoplasias/patologia , Animais , Progressão da Doença , Humanos , Hipóxia/metabolismo , Microdomínios da Membrana/metabolismo , Metástase NeoplásicaRESUMO
Epstein-Barr virus (EBV) is an important cancer causing virus. Cancer associated with EBV account for approximately 1.5% of all cancers, and represent 1.8% of all cancer deaths worldwide. EBV reactivation plays an important role in the development of EBV-related diseases and is closely related with patients' survival and clinical stages of EBV-related cancers. The therapy regarding to EBV-related cancers is very urgent, especially in endemic areas. Generating oxidative stress is a critical mechanism by which host cells defend against infection by virus. In addition, ROS-mediated oxidative stress plays a significant but paradoxical role acting as a "double-edged sword" to regulate cellular response to radiation, which is the main therapy strategy for EBV-related cancers, especially nasopharyngeal carcinoma. Therefore, in this review we primarily discuss the possible interplay among the oxidative stress, EBV lytic reactivation and radioresistance. Understanding the role of oxidative stress in EBV lytic reactivation and radioresistance will assist in the development of effective strategies for prevention and treatment of EBV-related cancers.
Assuntos
Carcinoma/genética , Infecções por Vírus Epstein-Barr/genética , Neoplasias Nasofaríngeas/genética , Estresse Oxidativo/genética , Tolerância a Radiação/genética , Carcinoma/patologia , Carcinoma/radioterapia , Carcinoma/virologia , Infecções por Vírus Epstein-Barr/patologia , Infecções por Vírus Epstein-Barr/radioterapia , Infecções por Vírus Epstein-Barr/virologia , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/patogenicidade , Herpesvirus Humano 4/efeitos da radiação , Interações Hospedeiro-Patógeno , Humanos , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/patologia , Neoplasias Nasofaríngeas/radioterapia , Neoplasias Nasofaríngeas/virologia , Estresse Oxidativo/efeitos da radiação , Ativação Viral/genética , Ativação Viral/efeitos da radiaçãoRESUMO
Recently, mutations in isocitrate dehydrogenase 1/2 (IDH1/2) were discovered in 70% of low-grade glioma and secondary glioblastoma multiforme. The discovery of an oncogenic function and the identification of onco-metabolites of IDH1/2 support new roles for metabolism in cancer. For example, some evidence indicates that IDH2 might also exhibit oncogenic functions by promoting cellular metabolism and cancer cell growth. We examined the association between IDH2 rs11540478 and lung cancer risk in 262 lung cancer patient cases and 602 healthy control subjects and also investigated the biological function of rs11540478 in vivo. We found that a higher risk was observed in lung cancer patient carriers of rs11540478 TT and CT compared with CC carriers (OR = 1.44; 95%CI = 1.04-2.00; P = 0.03). The frequency of IDH2 rs11540478 TT and CT carriers was decreased in healthy individuals between the ages of 50-77 compared to those aged 30-49 (OR = 0.67; 95%CI = 0.47-0.96; P = 0.03). Functional analysis showed the effect of rs11540478 on IDH2 expression and lung cancer cell viability, with higher IDH2 expression and cell viability among T allele compared with C allele. IDH2 mRNA was higher in peripheral blood lymphocytes from lung cancer patients compared to healthy subjects. Herein, for the first time we identified IDH2 rs11540478 as a new susceptibility locus for lung cancer. The effect of rs11540478 on mRNA expression of IDH2 and lung cancer cell viability might provide new insight for the genetic basis of lung cancer. © 2016 Wiley Periodicals, Inc.
Assuntos
Isocitrato Desidrogenase/genética , Neoplasias Pulmonares/genética , Polimorfismo de Nucleotídeo Único , Células A549 , Adulto , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Tumoral , Sobrevivência Celular , Feminino , Regulação Neoplásica da Expressão Gênica , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Neoalbaconol, derived from Albatrellus confluens, shows anti-cancer activities in the previously study, but its role in angiogenesis is unknown. Here, we determined whether neoalbaconol could attenuate angiogenesis and how does it occur. Data demonstrated that neoalbaconol could inhibit the proliferation of breast cancer cells and induce apoptosis. Also, neoalbaconol suppressed vascular endothelial growth factor (VEGF)-induced human umbilical vascular endothelial cells (HUVECs) proliferation, migration, invasion, and capillary-like tube formation in vitro and reduced tumor angiogenesis in vivo. VEGF receptor activation and the downstream signal transduction cascades activation were inhibited by neoalbaconol. Additionally, neoalbaconol blocked EGFR-mediated VEGF production. EGFR overexpression reversed the neoalbaconol-induced VEGF reduction, confirming the importance of the EGFR inhibition in anti-angiogenesis of neoalbaconol. Furthermore, neoalbaconol inhibited tumor growth and tumor angiogenesis in a breast cancer xenograft model in vivo. Taken together, these results indicate that neoalbaconol could inhibit tumor angiogenesis and growth through direct suppression effects on vascular endothelial cells and reduction of proangiogenic factors in cancer cells.
Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Receptores ErbB/metabolismo , Neovascularização Patológica/tratamento farmacológico , Sesquiterpenos/farmacologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Neoplasias da Mama/irrigação sanguínea , Neoplasias da Mama/patologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Receptores ErbB/genética , Feminino , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Camundongos Nus , Neovascularização Patológica/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Cancer incidence and mortality are increasing and impacting global life expectancy. Metabolic reprogramming in the tumor microenvironment (TME) is intimately related to tumorigenesis, progression, metastasis and drug resistance. Tumor cells drive metabolic reprogramming of other cells in the TME through metabolic induction of cytokines and metabolites, and metabolic substrate competition. Consequently, this boosts tumor cell growth by providing metabolic support and facilitating immunosuppression and angiogenesis. The metabolic interplay in the TME presents potential therapeutic targets. Here, we focus on the metabolic reprogramming of four principal cell subsets in the TME: CAFs, TAMs, TILs and TECs, and their interaction with tumor cells. We also summarize medications and therapies targeting these cells' metabolic pathways, particularly in the context of immune checkpoint blockade therapy.
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Circadian Locomotor Output Cycles Kaput (CLOCK) is one of the circadian clock genes and is considered to be a fundamental regulatory gene in the circadian rhythm, responsible for mediating several biological processes. Therefore, abnormal expression of CLOCK affects its role in the circadian clock and its more general function as a direct regulator of gene expression. This dysfunction can lead to severe pathological effects, including cancer. To better understand the role of CLOCK in cancer, we compiled this review to describe the biological function of CLOCK, and especially highlighted its function in cancer development, progression, tumor microenvironment, cancer cell metabolism, and drug resistance.
Assuntos
Proteínas CLOCK , Relógios Circadianos , Neoplasias , Microambiente Tumoral , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Relógios Circadianos/genética , Proteínas CLOCK/genética , Proteínas CLOCK/metabolismo , Microambiente Tumoral/genética , Regulação Neoplásica da Expressão Gênica , Ritmo Circadiano/genética , Animais , Resistencia a Medicamentos Antineoplásicos/genéticaRESUMO
Novel protein acylations are a class of protein post-translational modifications, such as lactylation, succinylation, crotonylation, palmitoylation, and ß-hydroxybutyrylation. These acylation modifications are common in prokaryotes and eukaryotes and play pivotal roles in various key cellular processes by regulating gene transcription, protein subcellular localization, stability and activity, protein-protein interactions, and protein-DNA interactions. The diversified acylations are closely associated with various human diseases, especially cancer. In this review, we provide an overview of the distinctive characteristics, effects, and regulatory factors of novel protein acylations. We also explore the various mechanisms through which novel protein acylations are involved in the occurrence and progression of cancer. Furthermore, we discuss the development of anti-cancer drugs targeting novel acylations, offering promising avenues for cancer treatment.
Assuntos
Antineoplásicos , Neoplasias , Processamento de Proteína Pós-Traducional , Humanos , Neoplasias/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Acilação , Animais , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologiaRESUMO
Abnormal expression of Cylindromatosis (CYLD), a tumor suppressor molecule, plays an important role in tumor development and treatment. In this work, we found that CYLD binds to class I histone deacetylases (HDAC1 and HDAC2) through its N-terminal domain and inhibits HDAC1 activity. RNA sequencing showed that CYLD-HDAC axis regulates cellular antioxidant response via Nrf2 and its target genes. Then we revealed a mechanism that class I HDACs mediate redox abnormalities in CYLD low-expressing tumors. HDACs are central players in the DNA damage signaling. We further confirmed that CYLD regulates radiation-induced DNA damage and repair response through inhibiting class I HDACs. Furthermore, CYLD mediates nasopharyngeal carcinoma cell radiosensitivity through class I HDACs. Thus, we identified the function of the CYLD-HDAC axis in radiotherapy and blocking HDACs by Chidamide can increase the sensitivity of cancer cells and tumors to radiation therapy both in vitro and in vivo. In addition, ChIP and luciferase reporter assays revealed that CYLD could be transcriptionally regulated by zinc finger protein 202 (ZNF202). Our findings offer novel insight into the function of CYLD in tumor and uncover important roles for CYLD-HDAC axis in radiosensitivity, which provide new molecular target and therapeutic strategy for tumor radiotherapy.
Assuntos
Inibidores de Histona Desacetilases , Neoplasias Nasofaríngeas , Humanos , Inibidores de Histona Desacetilases/farmacologia , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/radioterapia , Estresse Oxidativo , Histona Desacetilases/metabolismo , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/radioterapia , Enzima Desubiquitinante CYLD/genética , Enzima Desubiquitinante CYLD/metabolismo , Proteínas Repressoras/metabolismoRESUMO
Background: Ovarian cancer (OC) represents the seventh most lethal female tumors worldwide. The combination of PARP inhibitor (PARPi) and angiogenic inhibitor has been shown to be effective as a first-line or second-line maintenance regimen to synergistically exert antitumor effects, which prompts us to further evaluate the therapeutic effect of the combination of PARP inhibitor Niraparib and anti-angiogenic Brivanib on OC. Method:3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay were applied to evaluate the anti-proliferative effect of Niraparib, Brivanib, or the combination treatment on OC cells. The Annexin V-FITC/PI apoptotic assay was adopted to detect cell apoptosis. Tumor xenograft experiment and immunohistochemical (IHC) analysis were performed to evaluate the effect of single or combination treatment on the tumorigenicity of OC in vivo. Results: Our current findings revealed that OC cells harboring BRAC1/2 mutations were more sensitive to Niraparib treatment compared to those with BRAC wild-type, and the addition of Brivanib enhanced programmed cell death (PCD) to sensitize OC cells with BRAC mutations to Niraparib treatment in vitro and in vivo. Conclusion: Our work illustrates that the combination regimen of PARPi and angiogenic inhibitor treatment should be beneficial for the OC patients with BRAC mutations, at least partially owing to the induction of multiple forms of programmed cell death (PCD).
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The high prevalence of metabolic reprogramming in nasopharyngeal carcinoma (NPC) offers an abundance of potential therapeutic targets. This review delves into the distinct mechanisms underlying metabolic reprogramming in NPC, including enhanced glycolysis, nucleotide synthesis, and lipid metabolism. All of these changes are modulated by Epstein-Barr virus (EBV) infection, hypoxia, and tumor microenvironment. We highlight the role of metabolic reprogramming in the development of NPC resistance to standard therapies, which represents a challenging barrier in treating this malignancy. Furthermore, we dissect the state of the art in therapeutic strategies that target these metabolic changes, evaluating the successes and failures of clinical trials and the strategies to tackle resistance mechanisms. By providing a comprehensive overview of the current knowledge and future directions in this field, this review sets the stage for new therapeutic avenues in NPC.
Assuntos
Carcinoma , Infecções por Vírus Epstein-Barr , Neoplasias Nasofaríngeas , Humanos , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/patologia , Infecções por Vírus Epstein-Barr/complicações , Carcinoma/metabolismo , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patologia , Herpesvirus Humano 4/metabolismo , Microambiente TumoralRESUMO
Circadian rhythm refers to the inherent 24-h cycle oscillation of biochemical, physiological and behavioral functions, which is almost universal in eukaryotes. At least 14 core clock genes have been reported to form multiple chain feedback loops that confer intrinsic circadian rhythmicity onto the molecular clock. Accumulating evidence has shown that the circadian gene dysfunction resulted from single nucleotide polymorphisms (SNPs), deletions, epigenetic modification, and deregulation is strongly associated with cancer risk. In the present review, we describe the composition of circadian rhythm system. We highlight the function and mechanism of clock genes in cancer pathogenesis and progression. Moreover, their potential clinical implications as prognostic biomarkers and therapeutic targets have been addressed.
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Colorectal cancer (CRC) is a lethal malignancy with limited treatment strategies. Accumulating evidence indicates that CRC tumorigenesis, progression and metastasis are intimately associated with circadian clock, an inherent 24-h cycle oscillation of biochemical, physiological functions in almost every eukaryote. In the present review, we summarize the altered expression level of circadian genes in CRC and the prognosis associated with gene abundance switch. We illustrate the function and potential mechanisms of circadian genes in CRC pathogenesis and progression. Moreover, circadian based-therapeutic strategies including chronotherapy, therapeutics targeting potential circadian components, and melatonin treatment in CRC are also highlighted.
Assuntos
Relógios Circadianos , Neoplasias Colorretais , Humanos , Relógios Circadianos/genética , Carcinogênese , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Ritmo Circadiano/genéticaRESUMO
BACKGROUND: Epstein-Barr virus (EBV) is the first discovered human tumor virus that is associated with a variety of malignancies of both lymphoid and epithelial origin including nasopharyngeal carcinoma (NPC). The EBV-encoded latent membrane protein 1 (LMP1) has been well-defined as a potent oncogenic protein, which is intimately correlated with NPC pathogenesis. Anoikis is considered to be a physiological barrier to metastasis, and avoiding anoikis is a major hallmark of metastasis. However, the role of LMP1 in anoikis-resistance and metastasis of NPC has not been fully identified. METHODS: Trypan blue staining, colony formation assay, flow cytometry, and TUNEL staining, as well as the detection of apoptosis and anoikis resistance-related markers was applied to evaluate the anoikis-resistant capability of NPC cells cultured in ultra-low adhesion condition. Co-immunoprecipitation (Co-IP) experiment was performed to determine the interaction among LMP1, PRMT1 and PGC-1α. Ex vivo ubiquitination assay was used to detect the ubiquitination level of PGC-1α. Anoikis- resistant LMP1-positive NPC cell lines were established and applied for the xenograft and metastatic animal experiments. RESULTS: Our current findings reveal the role of LMP1-stabilized peroxisome proliferator activated receptor coactivator-1a (PGC-1α) in anoikis resistance and immune escape to support the invasion and metastasis of NPC. Mechanistically, LMP1 enhances PGC-1α protein stability by promoting the interaction between arginine methyltransferase 1 (PRMT1) and PGC-1α to elevate the methylation modification of PGC-1α, thus endowing NPC cells with anoikis-resistance. Meanwhile, PGC-1α mediates the immune escape induced by LMP1 by coactivating with STAT3 to transcriptionally up-regulate PD-L1 expression. CONCLUSION: Our work provides insights into how virus-encoded proteins recruit and interact with host regulatory elements to facilitate the malignant progression of NPC. Therefore, targeting PGC-1α or PRMT1-PGC-1α interaction might be exploited for therapeutic gain for EBV-associated malignancies.
Assuntos
Carcinoma , Infecções por Vírus Epstein-Barr , Neoplasias Nasofaríngeas , Animais , Humanos , Carcinoma Nasofaríngeo/genética , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/metabolismo , Anoikis , Neoplasias Nasofaríngeas/tratamento farmacológico , Proteínas de Membrana/metabolismo , Proteínas da Matriz Viral/genética , Proteínas da Matriz Viral/metabolismo , Linhagem Celular Tumoral , Proteína-Arginina N-Metiltransferases/metabolismo , Proteínas Repressoras/metabolismoRESUMO
Colorectal cancer (CRC) is one of the most common cancers worldwide, which ranks third in terms of incidence and the second leading cause of cancer-related mortality. Metabolic reprogramming within the tumor microenvironment (TME) has been proved intimately involved in the initiation and malignant progression of CRC. Signal messengers, including cytokines, metabolites, and exosomes among others, derived from cancer cells can be utilized by the surrounding cells within the TME to induce metabolic alteration and cancer-associated transformation. In turn, the cargos secreted from cancer-associate cells further provide the nutrition and energy supply for cancer cells, supporting their metabolic reprogramming to promote proliferation, migration, metastasis, and radiochemoresistance. In this review, we focus on the main cellular components in the TME: CAFs, TAMs, lymphocytes and neutrophils, and enumerate and integrate how the metabolic interactions between these components and cancer cells reshape TME to foster CRC malignancy.
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Neoplasias Colorretais , Exossomos , Linhagem Celular Tumoral , Neoplasias Colorretais/patologia , Citocinas/metabolismo , Exossomos/metabolismo , Humanos , Microambiente TumoralRESUMO
The short-chain dehydrogenase/reductase (SDR) superfamily has essential roles in lipid metabolism and redox sensing. In recent years, accumulating evidence highlights the emerging association between SDR family enzymes and cancer. Dehydrogenase/reductase member 2(DHRS2) belongs to the NADH/NADPH-dependent SDR family, and extensively participates in the regulation of the proliferation, migration, and chemoresistance of cancer cells. However, the underlying mechanism has not been well defined. In the present study, we have demonstrated that DHRS2 inhibits the growth and metastasis of ovarian cancer (OC) cells in vitro and in vivo. Mechanistically, the combination of transcriptome and metabolome reveals an interruption of choline metabolism by DHRS2. DHRS2 post-transcriptionally downregulates choline kinase α (CHKα) to inhibit AKT signaling activation and reduce phosphorylcholine (PC)/glycerophosphorylcholine (GPC) ratio, impeding choline metabolism reprogramming in OC. These actions mainly account for the tumor-suppressive role of DHRS2 in OC. Overall, our findings establish the mechanistic connection among metabolic enzymes, metabolites, and the malignant phenotype of cancer cells. This could result in further development of novel pharmacological tools against OC by the induction of DHRS2 to disrupt the choline metabolic pathway.