RESUMO
Fatty acid oxidation (FAO) fuels many cancers. However, knowledge of pathways that drive FAO in cancer remains unclear. Here, we revealed that valosin-containing protein (VCP) upregulates FAO to promote colorectal cancer growth. Mechanistically, nuclear VCP binds to histone deacetylase 1 (HDAC1) and facilitates its degradation, thus promoting the transcription of FAO genes, including the rate-limiting enzyme carnitine palmitoyltransferase 1A (CPT1A). FAO is an alternative fuel for cancer cells in environments exhibiting limited glucose availability. We observed that a VCP inhibitor blocked the upregulation of FAO activity and CPT1A expression triggered by metformin in colorectal cancer (CRC) cells. Combined VCP inhibitor and metformin prove more effective than either agent alone in culture and in vivo. Our study illustrates the molecular mechanism underlying the regulation of FAO by nuclear VCP and demonstrates the potential therapeutic utility of VCP inhibitor and metformin combination treatment for colorectal cancer.
Assuntos
Neoplasias Colorretais , Metformina , Humanos , Proteína com Valosina/genética , Proteína com Valosina/metabolismo , Processos Neoplásicos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Ácidos Graxos/metabolismo , Metformina/farmacologia , Carnitina O-Palmitoiltransferase/metabolismo , OxirreduçãoRESUMO
Lipopolysaccharide (LPS) is a toxic component of the outer membrane of gram-negative bacteria that can activate the blood coagulation system, leading to disseminated intravascular coagulation (DIC). DIC is a syndrome characterized by thromboembolism and multiple organ failure. Herein, the beneficial effect of paeoniflorin (PF) on the alleviation of LPS-induced DIC was investigated with an experimental DIC mouse model. Briefly, mice were randomly divided into the following six groups: (1) control; (2) LPS; (3) heparin; (4) low-PF treatment; (5) medium-PF treatment; and (6) high-PF treatment. The histological morphology of the liver and kidney was observed, and the coagulation indicators (such as prothrombin time), function indicators (such as alanine transferase), and inflammatory factors (such as TNF-α) were detected. Additionally, an in vitro cell inflammation model using RAW 264.7 murine macrophages was established. Activation of the nuclear factor kappa B (NF-κB) signaling pathway and tumor necrosis factor-α (TNF-α) were determined by western blotting. Based on our findings, PF could significantly improve the histological morphology of the liver and kidney, indicating that PF protects the liver and kidney against damage induced by LPS. Additionally, PF improved the function and coagulation indicators and reduced the production of inflammatory factors. In vitro, PF inhibited the expression of TNF-α by suppressing NF-κB signaling pathway activation. Collectively, our findings support the hypothesis that PF has anti-inflammatory and anticoagulation effects for the alleviation of LPS-induced DIC. PF is thus a potential co-treatment option for DIC.
Assuntos
Anti-Inflamatórios/farmacologia , Coagulação Intravascular Disseminada/tratamento farmacológico , Glucosídeos/farmacologia , Inflamação/tratamento farmacológico , Monoterpenos/farmacologia , Alanina Transaminase/metabolismo , Animais , Coagulação Sanguínea/efeitos dos fármacos , Modelos Animais de Doenças , Coagulação Intravascular Disseminada/fisiopatologia , Inflamação/patologia , Lipopolissacarídeos , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Camundongos , NF-kappa B/metabolismo , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Glioblastoma (GBM) is the deadliest form of brain cancer. It is a highly angiogenic and immunosuppressive malignancy. Although immune checkpoint blockade therapies have revolutionized treatment for many types of cancer, their therapeutic efficacy in GBM has been far less than expected or even ineffective. In this study, we found that the genomic signature of glioma-derived endothelial cells (GdEC) correlates with an immunosuppressive state and poor prognosis of patients with glioma. We established an in vitro model of GdEC differentiation for drug screening and used this to determine that cyclic adenosine monophosphate (cAMP) activators could effectively block GdEC formation by inducing oxidative stress. Furthermore, cAMP activators impaired GdEC differentiation in vivo, normalized the tumor vessels, and altered the tumor immune profile, especially increasing the influx and function of CD8+ effector T cells. Dual blockade of GdECs and PD-1 induced tumor regression and established antitumor immune memory. Thus, our study reveals that endothelial transdifferentiation of GBM shapes an endothelial immune cell barrier and supports the clinical development of combining GdEC blockade and immunotherapy for GBM. See related Spotlight by Lee et al., p. 1300.
Assuntos
Neoplasias Encefálicas , Glioblastoma , Glioma , Humanos , Glioblastoma/genética , Células Endoteliais , Linfócitos T/patologia , Neoplasias Encefálicas/genética , AMP Cíclico , ImunoterapiaRESUMO
Immune checkpoint blockade therapies are still ineffective for most patients with colorectal cancer (CRC). Immunogenic cell death (ICD) enables the release of key immunostimulatory signals to drive efficient anti-tumor immunity, which could be used to potentiate the effects of immune checkpoint inhibitors. Here, we showed that inhibition of valosin-containing protein (VCP) elicits ICD in CRC. Meanwhile, VCP inhibitor upregulates PD-L1 expression and compromises anti-tumor immunity in vivo. Mechanistically, VCP transcriptionally regulates PD-L1 expression in a JAK1-dependent manner. Combining VCP inhibitor with anti-PD1 remodels tumor immune microenvironment and reduces tumor growth in mouse models of CRC. Addition of oncolytic virus further augments the therapeutic activity of the combination regimen. Our study shows the molecular mechanism for regulating PD-L1 expression by VCP and suggests that inhibition of VCP has the potential to increase the efficacy of immunotherapy in CRC.
Assuntos
Neoplasias Colorretais , Vírus Oncolíticos , Animais , Camundongos , Humanos , Proteína com Valosina , Antígeno B7-H1 , Imunoterapia , Neoplasias Colorretais/tratamento farmacológico , Microambiente Tumoral , Linhagem Celular TumoralRESUMO
IDH1 mutations frequently occur early in human glioma. While IDH1 mutation has been shown to promote gliomagenesis via DNA and histone methylation, little is known regarding its regulation in antiviral immunity. Here, we discover that IDH1 mutation inhibits virus-induced interferon (IFN) antiviral responses in glioma cells. Mechanistically, D2HG produced by mutant IDH1 enhances the binding of DNMT1 to IRF3/7 promoters such that IRF3/7 are downregulated, leading to impaired type I IFN response in glioma cells, which enhances the susceptibility of gliomas to viral infection. Furthermore, we identify DNMT1 as a potential biomarker predicting which IDH1mut gliomas are most likely to respond to oncolytic virus. Finally, both D2HG and ectopic mutant IDH1 can potentiate the replication and oncolytic efficacy of VSVΔ51 in female mouse models. These findings reveal a pivotal role for IDH1 mutation in regulating antiviral response and demonstrate that IDH1 mutation confers sensitivity to oncolytic virotherapy.
Assuntos
Neoplasias Encefálicas , Glioma , Terapia Viral Oncolítica , Vírus Oncolíticos , Animais , Feminino , Humanos , Camundongos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Glioma/genética , Glioma/terapia , Glioma/metabolismo , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/metabolismo , Metilação , Mutação , Vírus Oncolíticos/genética , Vírus Oncolíticos/metabolismoRESUMO
Paclitaxel (PTX) is widely used in the treatment of nonsmall cell lung cancer (NSCLC). However, acquired PTX drug resistance is a major obstacle to its therapeutic efficacy and the underlying mechanisms are still unclear. The present study revealed a novel role of the SRYbox transcription factor 2 (SOX2)chloride voltagegated channel3 (ClC3) axis in PTX resistance of A549 NSCLC cells. The expression levels of SOX2 and ClC3 were upregulated in PTXresistant A549 NSCLC cells by RTqPCR and western blotting. The drug resistance to PTX of A549 NSCLC cells were measured by detecting the cell viability and the expression of drug resistance markers. Knockdown of SOX2 or ClC3 effectively decreased PTX resistance of A549 NSCLC cells, whereas SOX2 or ClC3 overexpression promoted PTX resistance. Mechanistically, SOX2 bound to the promoter of ClC3 and enhanced the transcriptional activation of ClC3 expression by CUT&Tag assays, CUT&Tag qPCR and luciferase reporter. In summary, the present findings defined ClC3 as an important downstream effector of SOX2 and ClC3 and SOX2 contributed to PTX resistance. Targeting SOX2 and its downstream effector ClC3 increased the sensitivity of NSCLC cells to PTX treatment, which provided potential therapeutic strategies for patients with NSCLC with PTX resistance.