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Proto-oncogenic MYC is frequently dysregulated in colorectal cancer (CRC). In the past decades, long noncoding RNAs (lncRNAs) have emerged as important regulators in cancers, acting as scaffolds, molecular decoys, post-transcriptional regulators, and others. Interestingly, lncRNAs are able to control MYC expression both at transcriptional and post-transcriptional levels. It is suggested that the reciprocal interaction of MYC and lncRNAs often occurs in CRC. MYC can affect the cell fate by promoting or inhibiting the transcription of some lncRNAs. At the same time, some lncRNAs can also affect MYC expression or transcriptional activity, and in turn decide the cell fate. In this review we summarized the current knowledge about the MYC and lncRNA axis, focusing on its mutual regulation, roles in CRC, and proposed potential therapeutic prospects for CRC treatment.
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Neoplasias Colorretais , Regulação Neoplásica da Expressão Gênica , Proteínas Proto-Oncogênicas c-myc , RNA Longo não Codificante , Humanos , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , AnimaisRESUMO
Interleukin-22 (IL-22) is a vital cytokine that is dysregulated in various autoimmune conditions including rheumatoid arthritis (RA), multiple sclerosis (MS), and Alzheimer's disease (AD). As the starting point for the activation of numerous signaling pathways, IL-22 plays an important role in the initiation and development of autoimmune diseases. Specifically, imbalances in IL-22 signaling can interfere with other signaling pathways, causing cross regulation of target genes which ultimately leads to the development of immune disorders. This review delineates the various connections between the IL-22 signaling pathway and autoimmune disease, focusing on the latest understanding of the cellular sources of IL-22 and its effects on various cell types. We further explore progress with pharmacological interventions related to targeting IL-22, describing how such therapeutic strategies promise to usher in a new era in the treatment of autoimmune disease.
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The efficacy of immunotherapy against colorectal cancer (CRC) is impaired by insufficient immune cell recruitment into the tumor microenvironment. Our study shows that targeting circDNA2v, a circular RNA commonly overexpressed in CRC, can be exploited to elicit cytotoxic T cell recruitment. circDNA2v functions through binding to IGF2BP3, preventing its ubiquitination, and prolonging the IGF2BP3 half-life, which in turn sustains mRNA levels of the protooncogene c-Myc. Targeting circDNA2v by gene silencing downregulates c-Myc to concordantly induce tumor cell senescence and the release of proinflammatory mediators. Production of CXCL10 and interleukin-9 by CRC cells is elicited through JAK-STAT1 signaling, in turn promoting the chemotactic and cytolytic activities of CD8+ T cells. Clinical evidence associates increased circDNA2v expression in CRC tissues with reductions in CD8+ T cell infiltration and worse outcomes. The regulatory relationship between circDNA2v, cellular senescence, and tumor-infiltrating lymphocytes thus provides a rational approach for improving immunotherapy in CRC.
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Senescência Celular , Neoplasias Colorretais , Humanos , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , RNA Circular/genética , RNA Circular/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Linhagem Celular Tumoral , Animais , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Camundongos , Transdução de Sinais , Regulação Neoplásica da Expressão Gênica , Microambiente Tumoral/imunologia , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Fator de Transcrição STAT1/metabolismoRESUMO
More than half of all cancers demonstrate aberrant c-Myc expression, making this arguably the most important human oncogene. Deregulated long non-coding RNAs (lncRNAs) are also commonly implicated in tumorigenesis, and some limited examples have been established where lncRNAs act as biological tuners of c-Myc expression and activity. Here, we demonstrate that the lncRNA denoted c-Myc Enhancing Factor (MEF) enjoys a cooperative relationship with c-Myc, both as a transcriptional target and driver of c-Myc expression. Mechanistically, MEF functions by binding to and stabilizing the expression of hnRNPK in colorectal cancer cells. The MEF-hnRNPK interaction serves to disrupt binding between hnRNPK and the E3 ubiquitin ligase TRIM25, which attenuates TRIM25-dependent hnRNPK ubiquitination and proteasomal destruction. In turn, the stabilization of hnRNPK through MEF enhances c-Myc expression by augmenting the translation c-Myc. Moreover, modulating the expression of MEF in shRNA-mediated knockdown and overexpression studies revealed that MEF expression is essential for colorectal cancer cell proliferation and survival, both in vitro and in vivo. From the clinical perspective, we show that MEF expression is differentially increased in colorectal cancer tissues compared to normal adjacent tissues. Further, correlations exist between MEF, c-Myc, and hnRNPK suggesting the MEF-c-Myc positive feedback loop is active in patients. Together these data demonstrate that MEF is a pivotal partner of the c-Myc network and propose MEF as a valuable therapeutic target for colorectal cancer.
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Neoplasias Colorretais , RNA Longo não Codificante , Humanos , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Regulação Neoplásica da Expressão Gênica , Transformação Celular Neoplásica/genética , Carcinogênese/genética , Neoplasias Colorretais/metabolismo , Proliferação de Células/genética , Linhagem Celular TumoralRESUMO
Cytochrome P450 3A4 (CYP3A4) is the most important and abundant drug-metabolizing enzyme in the human liver. Inter-individual differences in the expression and activity of CYP3A4 affect clinical and precision medicine. Increasing evidence indicates that long noncoding RNAs (lncRNAs) play crucial roles in the regulation of CYP3A4 expression. Here, we showed that lncRNA hepatocyte nuclear factor 1 alpha-antisense 1 (HNF1A-AS1) exerted dual functions in regulating CYP3A4 expression in Huh7 and HepG2 cells. Mechanistically, HNF1A-AS1 served as an RNA scaffold to interact with both protein arginine methyltransferase 1 and pregnane X receptor (PXR), thereby facilitating their protein interactions and resulting in the transactivation of PXR and transcriptional alteration of CYP3A4 via histone modifications. Furthermore, HNF1A-AS1 bound to the HNF1A protein, a liver-specific transcription factor, thereby blocking its interaction with the E3 ubiquitin ligase tripartite motif containing 25, ultimately preventing HNF1A ubiquitination and protein degradation, further regulating the expression of CYP3A4. In summary, these results reveal the novel functions of HNF1A-AS1 as the transcriptional and post-translational regulator of CYP3A4; thus, HNF1A-AS1 may serve as a new indicator for establishing or predicting individual differences in CYP3A4 expression.
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RNA Longo não Codificante , Humanos , Citocromo P-450 CYP3A/genética , Regulação da Expressão Gênica , Fator 1-alfa Nuclear de Hepatócito/genética , Fígado , RNA Longo não Codificante/genéticaRESUMO
[This corrects the article on p. 1019 in vol. 8, PMID: 30034939.].
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Colorectal cancer (CRC) poses one of the most serious threats to human health worldwide, and abnormally expressed c-Myc and p53 are deemed the pivotal driving forces of CRC progression. In this study, we discovered that the lncRNA FIT, which was downregulated in CRC clinical samples, was transcriptionally suppressed by c-Myc in vitro and promoted CRC cell apoptosis by inducing FAS expression. FAS is a p53 target gene, and we found that FIT formed a trimer with RBBP7 and p53 that facilitated p53 acetylation and p53-mediated FAS gene transcription. Moreover, FIT was capable of retarding CRC growth in a mouse xenograft model, and FIT expression was positively correlated with FAS expression in clinical samples. Thus, our study elucidates the role of the lncRNA FIT in human colorectal cancer growth and provides a potential target for anti-CRC drugs.
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Neoplasias Colorretais , RNA Longo não Codificante , Humanos , Animais , Camundongos , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Acetilação , RNA Longo não Codificante/genética , Proliferação de Células/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Carcinogênese/genética , Regulação Neoplásica da Expressão Gênica , Linhagem Celular Tumoral , Proteína 7 de Ligação ao Retinoblastoma/genética , Proteína 7 de Ligação ao Retinoblastoma/metabolismoRESUMO
Around 70 % of patients diagnosed with acute myeloid leukemia (AML) survive less than 5 years due to drug resistance and disease relapse. Consequently, improved clinical treatments are urgently needed. Some but not all AML patients benefit from the combination of the BCL-2 inhibitor Venetoclax with the hypomethylation agent Azacitidine. Here we investigated the utility of employing the cyclin dependent kinase (CDK6) inhibitor Palbociclib to improve the efficacy of Venetoclax/Azacitidine combination therapy. Our analysis of publicly available RNA sequencing datasets showed CDK6 was highly expressed in the major acute forms of leukemia including AML. Consistently, using qPCR and flow cytometry we found that CDK6 was overexpressed in bone marrow mononuclear cells from AML patients compared to healthy controls. Subsequent in vitro testing of Palbociclib, Venetoclax and Azacitidine, alone and in combination against CDK6-overexpressing AML cells lines THP-1 and KG-1 and primary AML cells showed that the Palbociclib/Venetoclax/Azacitidine combination improved treatment efficacy compared to Venetoclax/Azacitidine treatment alone. Additional investigations in a subcutaneous KG-1 mouse model showed similarly the three-drug combination produced the most significant reductions in tumor load together with the least amount of spleen infiltration. We established Palbociclib functioned in combination with Venetoclax/Azacitidine by increasing the rates of apoptosis in AML cells. Further investigations revealed that Palbociclib does not affect BCL-2 activity but downregulated the anti-apoptotic proteins MCL-1 and BCL-XL, making AML cells more sensitive to Venetoclax/Azacitidine treatment. Our results propose that the Palbociclib/Venetoclax/Azacitidine regimen warrants further preclinical research for clinical application in AML patients.
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Azacitidina , Leucemia Mieloide Aguda , Piperazinas , Piridinas , Animais , Azacitidina/farmacologia , Azacitidina/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Camundongos , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Piridinas/farmacologia , Piridinas/uso terapêutico , SulfonamidasRESUMO
Fascin actin-bundling protein 1 (FSCN1) is an actin-bundling protein that is capable of inducing membrane protrusions and plays critical roles in cell migration, motility, adhesion, and other cellular interactions. FSCN1 also plays a role in forming and stabilizing filopodia or microspikes, which assist during cell migration. Furthermore, FSCN1 is a downstream target of several microRNAs and participates in various biological processes, such as epithelial-to-mesenchymal transition and autophagy, which regulate the invasion and migration ability of cells in various cancers. Increased FSCN1 levels have been associated with enhanced migration and invasion of multiple cancers as well as poor patient prognosis. Promising results from in vitro experimental studies using docosahexaenoic acid (DHA) in breast cancer and recombinant porcine NK-lysin A in hepatocellular carcinoma have revealed that anticancer drugs targeting FSCN1 have significant potential clinical applications. This review discusses FSCN1 in terms of five aspects: structure and function, biological processes, regulatory mechanisms, clinical applications, and future prospects.
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PURPOSE: Radioresistance is a major cause of treatment failure in tumor radiation therapy, and the underlying mechanisms of radioresistance are still elusive. Golgi phosphoprotein 3 (GOLPH3) has been reported to associate tightly with cancer progression and chemoresistance. Herein, we explored whether GOLPH3 mediated radioresistance of lung adenocarcinoma (LUAD) and whether targeted suppression of GOLPH3 sensitized LUAD to radiation therapy. METHODS AND MATERIALS: The aberrant expression of GOLPH3 was evaluated by immunohistochemistry in LUAD clinical samples. To evaluate the association between GOLPH3 and radioresistance, colony formation and apoptosis were assessed in control and GOLPH3 knockdown cells. γ-H2AX foci and level determination and micronucleus test were used to analyze DNA damage production and repair. The rescue of GOLPH3 knockdown was then performed by exogenous expression of small interfering RNA-resistant mutant GOLPH3 to confirm the role of GOLPH3 in DNA damage repair. Mechanistically, the effect of GOLPH3 on regulating stability and nuclear accumulation of epidermal growth factor receptor (EGFR) and the activation of DNA-dependent protein kinase (DNA-PK) were investigated by quantitative real-time polymerase chain reaction, western blot, immunofluorescence, and coimmunoprecipitation. The role of GOLPH3 in vivo in radioresistance was determined in a xenograft model. RESULTS: In tumor tissues of 33 patients with LUAD, the expression of GOLPH3 showed significant increases compared with those in matched normal tissues. Knocking down GOLPH3 reduced the clonogenic capacity, impaired double-strand break (DSB) repair, and enhanced apoptosis after irradiation. In contrast, reversal of GOLPH3 depletion rescued the impaired repair of radiation-induced DSBs. Mechanistically, loss of GOLPH3 accelerated the degradation of EGFR in lysosome, causing the reduction in EGFR levels, thereby weakening nuclear accumulation of EGFR and attenuating the activation of DNA-PK. Furthermore, adenovirus-mediated GOLPH3 knockdown could enhance the ionizing radiation response in the LUAD xenograft model. CONCLUSIONS: GOLPH3 conferred resistance of LUAD to ionizing radiation via stabilizing EGFR, and targeted suppression of GOLPH3 might be considered as a potential therapeutic strategy for sensitizing LUAD to radiation therapy.
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Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/radioterapia , Apoptose/efeitos da radiação , Linhagem Celular Tumoral , DNA , Reparo do DNA , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/radioterapia , Proteínas de Membrana/genética , Fosfoproteínas/genética , Fosfoproteínas/farmacologia , Fosfoproteínas/uso terapêutico , Tolerância a Radiação/genéticaRESUMO
Colorectal cancer (CRC) is still one of the leading causes of cancer-associated death in the modern society. The biological function of miR-202-5p for CRC development remains controversial, largely due to the fact that miR-202-5p can be tumor-suppressive or oncogenic in different contexts. Obtained results indicated that aberrant expression of miR-202-5p was observed in majority of human CRC samples and miR-202-5p was transcriptionally up-regulated by c-Myc. In addition, miR-202-5p functions to promote the activation of PI3K/Akt signaling pathway by directly suppressing PTEN. Silencing or enforced expression of miR-202-5p resulted in CRC cell proliferation inhibition and enhancement, respectively. Importantly, decreased PTEN level and increased phosphorylation of Akt were frequently associated with elevated miR-202-5p expression in colorectal cancer tissues. Increased miR-202-5p expression may serve as a tumor promoter by directly targeting PTEN in colorectal cancer.
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Photocatalytic organic synthesis is mostly limited by the shortcomings of insufficient light absorption, high photogenerated electron-hole recombination rate and inadequate reactive sites of photocatalysts. To solve these problems, phosphorus-doped g-C3N4 with a porous structure was constructed. Benefiting from enhanced light absorption and electron-hole separation efficiency, PCNT has intensive oxygen activation ability to generate superoxide radicals, and is highly active in organic synthesis. In addition, PCNT has enhanced surface nucleophilicity, which is conducive to the carbon-carbon coupling process of the intermediate product benzaldehyde molecules and benzyl alcohol molecules in the benzoin condensation reaction. Metal-free PCNT is expected to replace the previously used highly toxic cyanide catalysts and provide a new way for the low-cost and efficient photocatalytic synthesis of benzoin.
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Many cancer cells maintain enhanced aerobic glycolysis due to irreversible defective mitochondrial oxidative phosphorylation (OXPHOS). This phenomenon, known as the Warburg effect, is recently challenged because most cancer cells maintain OXPHOS. However, how cancer cells coordinate glycolysis and OXPHOS remains largely unknown. Here, we demonstrate that OMA1, a stress-activated mitochondrial protease, promotes colorectal cancer development by driving metabolic reprogramming. OMA1 knockout suppresses colorectal cancer development in AOM/DSS and xenograft mice models of colorectal cancer. OMA1-OPA1 axis is activated by hypoxia, increasing mitochondrial ROS to stabilize HIF-1α, thereby promoting glycolysis in colorectal cancer cells. On the other hand, under hypoxia, OMA1 depletion promotes accumulation of NDUFB5, NDUFB6, NDUFA4, and COX4L1, supporting that OMA1 suppresses OXPHOS in colorectal cancer. Therefore, our findings support a role for OMA1 in coordination of glycolysis and OXPHOS to promote colorectal cancer development and highlight OMA1 as a potential target for colorectal cancer therapy.
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Neoplasias Colorretais , Fosforilação Oxidativa , Animais , Ciclo do Ácido Cítrico , Neoplasias Colorretais/genética , Glicólise , Hipóxia/genética , CamundongosRESUMO
Spindle and kinetochore-associated complex subunit 3 (SKA3) is a well-known regulator of chromosome separation and cell division, which plays an important role in cell proliferation. However, the mechanism of SKA3 regulating tumor proliferation via reprogramming metabolism is unknown. Here, SKA3 is identified as an oncogene in laryngeal squamous cell carcinoma (LSCC), and high levels of SKA3 are closely associated with malignant progression and poor prognosis. In vitro and in vivo experiments demonstrate that SKA3 promotes LSCC cell proliferation and chemoresistance through a novel role of reprogramming glycolytic metabolism. Further studies reveal the downstream mechanisms of SKA3, which can bind and stabilize polo-like kinase 1 (PLK1) protein via suppressing ubiquitin-mediated degradation. The accumulation of PLK1 activates AKT and thus upregulates glycolytic enzymes HK2, PFKFB3, and PDK1, resulting in enhancement of glycolysis. Furthermore, our data reveal that phosphorylation at Thr360 of SKA3 is critical for its binding to PLK1 and the increase in glycolysis. Collectively, the novel oncogenic signal axis "SKA3-PLK1-AKT" plays a critical role in the glycolysis of LSCC. SKA3 may serve as a prognostic biomarker and therapeutic target, providing a potential strategy for proliferation inhibition and chemosensitization in tumors, especially for LSCC patients with PLK1 inhibitor resistance.
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Biomarcadores Tumorais/metabolismo , Proteínas de Ciclo Celular/metabolismo , Neoplasias Laríngeas/tratamento farmacológico , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Animais , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos , Glicólise , Xenoenxertos , Humanos , Neoplasias Laríngeas/genética , Neoplasias Laríngeas/metabolismo , Neoplasias Laríngeas/patologia , Masculino , Camundongos , Camundongos Knockout , Camundongos Nus , Terapia de Alvo Molecular , Transdução de Sinais , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Quinase 1 Polo-LikeRESUMO
Head and neck cancer (HNC), which includes epithelial malignancies of the upper aerodigestive tract (oral cavity, oropharynx, pharynx, hypopharynx, larynx, and thyroid), are slowly but consistently increasing, while the overall survival rate remains unsatisfactory. Because of the multifunctional anatomical intricacies of the head and neck, disease progression and therapy-related side effects often severely affect the patient's appearance and self-image, as well as their ability to breathe, speak, and swallow. Patients with HNC require a multidisciplinary approach involving surgery, radiation therapy, and chemotherapeutics. Chemotherapy is an important part of the comprehensive treatment of tumors, especially advanced HNC, but drug resistance is the main cause of poor clinical efficacy. The most important determinant of this phenomenon is still largely unknown. Recent studies have shown that non-coding RNAs have a crucial role in HNC drug resistance. In addition, they can serve as biomarkers in the diagnosis, treatment, and prognosis of HNCs. In this review, we summarize the relationship between non-coding RNAs and drug resistance of HNC, and discuss their potential clinical application in overcoming HNC chemoresistance.
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Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , RNA não Traduzido/genética , Antineoplásicos/farmacologia , Biomarcadores Tumorais/genética , Progressão da Doença , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/patologia , Humanos , PrognósticoRESUMO
BACKGROUND: Recent studies revealed that miR-424-5p regulates the malignant behavior of multiple cancer types. However, the expression and function of miR-424-5p in laryngeal squamous cell carcinoma (LSCC) is unclear. PURPOSE: This study aimed to evaluate the association of miR-424-5p level with clinical features of LSCC and investigate the effect and potential mechanism of miR-424-5p on LSCC progression. METHODS: The expression of miR-424-5p in LSCC and paired adjacent normal margin (ANM) tissues from 106 patients with LSCC were analyzed by quantitative PCR (qPCR), and clinical significance was analyzed. Target genes of miR-424-5p were predicted, followed by functional annotation. The functional role of miR-424-5p in LSCC was investigated by molecular and cellular experiments with LSCC cell lines, with flow cytometry used for cell cycle analysis. In addition, miR-424-5p regulation of the predicted target gene cell adhesion molecule 1 (CADM1) was validated by qPCR, Western blot analysis and luciferase reporter assay. RESULTS: miR-424-5p was upregulated in LSCC versus ANM tissues. High miR-424-5p level was significantly associated with poor differentiation, advanced tumor stage and cervical lymph node metastasis. Bioinformatics analysis showed that miR-424-5p target genes are mainly enriched in biological processes of the cell cycle, cell division, and negative regulation of cell migration, and were involved in multiple cancer-related pathways. Overexpression of miR-424-5p promoted proliferation, migration, invasion, and adhesion of LSCC cells and affected the cell cycle progression. Additionally, CADM1 was a direct target of miR-424-5p in LSCC cells. CONCLUSION: miR-424-5p functions as an oncogene to promote the aggressive progression of LSCC, and CADM1 is a direct downstream target of miR-424-5p in LSCC cells. miR-424-5p may be a potential therapeutic target in LSCC.
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The tumor suppressor gene Tp53 encodes p53, a pivotal transcription factor with a broad target gene repertoire. Induction and stabilization of p53 during DNA damage and oncogene activation function to induce cell cycle arrest, apoptosis, or senescence. These actions are a failsafe to counteract carcinogenesis but Tp53 also plays a key role in regulating different aspects of cell metabolism including autophagy. Autophagy or cellular "self-eating" involves the dismantling and remodeling of cellular components, activities which are fundamental in maintaining cellular homeostasis and in supporting cell growth. After providing an historical overview of Tp53 research, the purpose of this chapter is to review the different mechanistic aspects of Tp53's role in autophagy and to highlight the key challenges which lie ahead. Tp53 functions are regulated by tight control of its cellular levels and notably, Tp53 can be both an activator or inhibitor of autophagy. Under stress conditions such as nutrient depletion or hypoxia, Tp53 contributes to autophagic activation by inhibiting mTOR signaling. Alternatively, p53 can interact with death-associated protein kinase 1 (DAPK1), acting to stabilize nuclear p53 amongst other functions including activation of the key autophagic mediator, Beclin-1. Under normal physiological conditions, Tp53 can inhibit autophagosome formation but stress conditions can also result in Tp53-mediated promotion of autophagy, demonstrating that Tp53 actions are highly context dependent. Tp53 target genes also play key opposing roles in autophagy induction or inhibition such as DRAM and TIGAR, respectively. Finally, the role of Tp53 mutants in autophagy regulation are discussed.
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Proteínas Reguladoras de Apoptose , Autofagia , Proteínas de Membrana , Proteína Supressora de Tumor p53 , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Humanos , Proteínas de Membrana/metabolismo , Monoéster Fosfórico Hidrolases , Transdução de Sinais , Proteína Supressora de Tumor p53/metabolismoRESUMO
The incidence of melanoma is increasing rapidly worldwide. Additionally, new and effective candidates for treating melanoma are needed because of the increase in drug resistance and the high metastatic potential of this cancer. The STAT3 signaling pathway plays a pivotal role in pathogenesis of melanoma, making STAT3 a promising anticancer target for melanoma therapy. Niclosamide, an FDA-approved anti-helminthic drug, has been identified as a potent STAT3 inhibitor that suppresses STAT3 phosphorylation at Tyr705 and its transcript activity. In this study, we evaluated the biological activities of niclosamide in melanoma in vitro and in vivo. Niclosamide potently inhibited the growth of four melanoma cell lines and induced the apoptosis of melanoma cells via the mitochondrial apoptotic pathway. Further, western blot analysis indicated that cell apoptosis was correlated with activation of Bax and cleaved caspase-3 and decreased expression of Bcl-2. Moreover, niclosamide markedly impaired melanoma cell migration and invasion, reduced phosphorylated STAT3Tyr705 levels, and inhibited matrix metalloproteinase-2 and -9 expression. Additionally, in a xenograft model of A375, intraperitoneal administration of niclosamide inhibited tumor growth and tumor weight in a dose-dependent manner without obvious side effects. Histological and immunohistochemical analyses revealed a decrease in Ki-67-positive cells and p-STAT3Try705-positive cells and increase in cleaved caspase-3-positive cells. Notably, niclosamide significantly inhibited pulmonary metastasis in a B16-F10 melanoma lung metastasis model, including the number of lung metastatic nodules and lung/body coefficient. Importantly, a marked reduction in myeloid-derived suppressor cells (Gr1+CD11b+) infiltration in the pulmonary metastasis tissue was observed. Taken together, these results demonstrate that niclosamide is a promising candidate for treating melanoma.
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Anti-Helmínticos/farmacologia , Reposicionamento de Medicamentos , Neoplasias Pulmonares/secundário , Melanoma Experimental/tratamento farmacológico , Niclosamida/farmacologia , Fator de Transcrição STAT3/fisiologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/prevenção & controle , Melanoma Experimental/patologia , Melanoma Experimental/secundário , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Células Supressoras Mieloides/fisiologia , Niclosamida/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologiaRESUMO
We report that circACC1, a circular RNA derived from human ACC1, plays a critical role in cellular responses to metabolic stress. CircACC1 is preferentially produced over ACC1 in response to serum deprivation by the transcription factor c-Jun. It functions to stabilize and promote the enzymatic activity of the AMPK holoenzyme by forming a ternary complex with the regulatory ß and γ subunits. The cellular levels of circACC1 modulate both fatty acid ß-oxidation and glycolysis, resulting in profound changes in cellular lipid storage. In a tumor xenograft model, silencing or enforced expression of circACC1 resulted in growth inhibition and enhancement, respectively. Moreover, increased AMPK activation in colorectal cancer tissues was frequently associated with elevated circACC1 expression. We conclude that circACC1 serves as an economic means to elicit AMPK activation and moreover propose that cancer cells exploit circACC1 during metabolic reprogramming.