RESUMO
Bisphenol A (BPA) has been a substantial additive in plastics until the reports on its adverse effects have led to its restrictions and replacement. Monitoring studies document the increasing occurrence of bisphenol analogs, however, data on their effects and risks is still insufficient. Based on the indications that BPA might contribute to ovarian cancer pathogenesis, we examined effects of the analogs AF (BPAF), S (BPS) and F (BPF) (10-9-10-4 M) on the Caov-3 epithelial cancer cells, including the impact on cell viability, proliferation, oxidative stress, and production and expression of several factors and genes related to ovarian cancer. At environmentally relevant doses, bisphenols did not exert significant effects. At the highest concentration, BPAF caused varied alterations, including decreased cell viability and proliferation, caspase activation, down-regulation of PCNA and BIRC5, elevation of IL8, VEGFA, MYC, PTGS2 and ABCB1 expressions. Only BPA (10-4 M) increased IL-6, IL-8 and VEGFA output by the Caov-3 cells. Each bisphenol induced generation of reactive oxygen species and decreased superoxide dismutase activity at the highest concentration. Although the effects were observed only in the supraphysiological doses, the results indicate that certain bisphenol analogs might affect several ovarian cancer cell characteristics and merit further investigation.
Assuntos
Compostos Benzidrílicos , Proliferação de Células , Sobrevivência Celular , Neoplasias Ovarianas , Fenóis , Humanos , Fenóis/toxicidade , Compostos Benzidrílicos/toxicidade , Proliferação de Células/efeitos dos fármacos , Feminino , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Linhagem Celular Tumoral , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Sulfonas/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Antígeno Nuclear de Célula em Proliferação/metabolismo , Antígeno Nuclear de Célula em Proliferação/genética , Survivina/genética , Survivina/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Interleucina-8/metabolismo , Interleucina-8/genética , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas Inibidoras de Apoptose/genética , Proteínas Inibidoras de Apoptose/metabolismo , FluorocarbonosRESUMO
Intratumoral delivery of mRNA encoding immunostimulatory molecules can initiate a robust, global antitumor response with little side effects by enhancing local antigen presentation in the tumor and the tumor draining lymph node. Neoantigen-based mRNA nanovaccine can inhibit melanoma growth in mice by intratumoral injection. Myeloid-derived suppressor cells (MDSCs) suppress antitumor immune responses by secreting immunosuppressive agents, such as reactive oxygen species (ROS). Suppression of STAT3 activity by stattic may reduce MDSC-mediated immunosuppression in the TME and promote the antitumor immune responses. In this study, in vitro transcribed mRNA encoding tumor antigen survivin was prepared and injected intratumorally in BALB/c mice bearing subcutaneous colon cancer tumors. In vivo studies demonstrated that intratumoral survivin mRNA therapy could induce antitumor T cell response and inhibit tumor growth of colon cancer. Depletion of CD8+ T cells could significantly inhibit survivin mRNA-induced antitumor effects. RT-qPCR and ELISA analysis indicated that survivin mRNA treatment led to increased expression of receptor activator nuclear factor-κB ligand (RANKL). In vitro experiment showed that MDSCs could be induced from mouse bone marrow cells by RANKL and RANKL-induced MDSCs could produce high level of ROS. STAT3 inhibitor stattic suppressed activation of STAT3 and NF-κB signals, thereby inhibiting expansion of RANKL-induced MDSCs. Combination therapy of survivin mRNA and stattic could significantly enhance antitumor T cell response, improve long-term survival and reduce immunosuppressive tumor microenvironment compared to each monotherapy. In addition, combined therapy resulted in a significantly reduced level of tumor cell proliferation and an obviously increased level of tumor cell apoptosis in CT26 colon cancer-bearing mice, which could be conducive to inhibit the tumor growth and lead to immune responses to released tumor-associated antigens. These studies explored intratumoral mRNA therapy and mRNA-based combined therapy to treat colon cancer and provide a new idea for cancer therapy.
Assuntos
Neoplasias do Colo , Óxidos S-Cíclicos , Camundongos Endogâmicos BALB C , RNA Mensageiro , Fator de Transcrição STAT3 , Survivina , Animais , Survivina/genética , Survivina/antagonistas & inibidores , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/metabolismo , RNA Mensageiro/genética , Neoplasias do Colo/terapia , Neoplasias do Colo/imunologia , Neoplasias do Colo/patologia , Neoplasias do Colo/genética , Óxidos S-Cíclicos/farmacologia , Linhagem Celular Tumoral , Injeções Intralesionais , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Camundongos , Feminino , Espécies Reativas de Oxigênio/metabolismo , Linfócitos T CD8-Positivos/imunologia , Proliferação de Células , Proteínas Inibidoras de Apoptose/genética , Proteínas Inibidoras de Apoptose/antagonistas & inibidores , Humanos , Carga Tumoral/efeitos dos fármacos , Transdução de SinaisRESUMO
We aimed to explore the role of regulating Smac expression levels in the occurrence and development of colon cancer through in vitro and in vivo experiments. Colon cancer cells HT-29 were cultured and transfected into different groups. qRT-PCR was used to detect the expression level of Smac in cells; Flow cytometry was used to detect the apoptotic ability of each group of cells; Western blot was used to detect the protein expression of Smac and apoptosis-related factors Survivin and Caspase-3; The nude mouse tumorigenesis experiment was conducted to detect the regulatory effect of regulating Smac expression levels on the growth of colon cancer transplanted tumors in vivo. In comparison to the FHC group, the HT-29 group exhibited a decrease in Smac expression. The si-Smac group, when compared with the si-NC group, showed significant reductions in Smac mRNA and protein levels, weaker cell apoptosis, increased Survivin, and decreased Caspase-3 expression. Contrarily, the oe-Smac group, against the oe-NC group, displayed increased Smac mRNA and protein levels, enhanced apoptosis, reduced Survivin, and elevated Caspase-3 expression. In nude mice tumor transplantation experiments, the LV-sh-Smac group, as opposed to the LV-sh-NC group, had tumors with greater volume and weight, reduced Smac and Caspase-3, and increased Survivin expression. In contrast, the LV-oe-Smac group, compared with the LV-oe-NC group, showed tumors with decreased volume and mass, increased expressions of Smac and Caspase-3, and decreased Survivin. Smac is lowly expressed in colon cancer. Upregulation of Smac expression can inhibit the occurrence and development of colon cancer, possibly by inhibiting Survivin expression and promoting Caspase-3 expression, thereby enhancing the pro-apoptotic function.
Assuntos
Proteínas Reguladoras de Apoptose , Apoptose , Caspase 3 , Neoplasias do Colo , Regulação Neoplásica da Expressão Gênica , Peptídeos e Proteínas de Sinalização Intracelular , Camundongos Nus , Proteínas Mitocondriais , Survivina , Animais , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Neoplasias do Colo/metabolismo , Humanos , Proteínas Reguladoras de Apoptose/metabolismo , Proteínas Reguladoras de Apoptose/genética , Apoptose/genética , Proteínas Mitocondriais/metabolismo , Proteínas Mitocondriais/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Survivina/metabolismo , Survivina/genética , Caspase 3/metabolismo , Caspase 3/genética , Células HT29 , Camundongos , Proteínas Inibidoras de Apoptose/genética , Proteínas Inibidoras de Apoptose/metabolismo , Camundongos Endogâmicos BALB C , Proliferação de Células/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
Inhibitors of Apoptosis proteins (IAPs) were discovered through experiments aimed at rescuing apoptosis in insects. Classically associated with the inhibition of apoptosis, the IAP member Survivin also regulates cell cycle progression and is an essential component of the Chromosomal Passenger Complex (CPC), responsible for chromosomal segregation. Although undetectable in most adult tissues, Survivin is expressed in Adult Stem Cells (ASCs) and plays a crucial role in their maintenance. Survivin is overexpressed in most cancers, contributing to their clonal expansion. As a result, it has been proposed as a possible anticancer target for nearly two decades. In this discussion, we will explore the rationale behind Survivin as a therapeutic target, focusing on common cancer types such as carcinomas, sarcomas, and leukemias. We will delve into the modulation of Survivin by cancer pro-survival cell signaling, the association between SNPs and tumorigenesis, and its regulation by miRNAs. Finally, we will compare cell growth, clonogenic capacity, and apoptosis, along with different strategies for Survivin inhibition, including gene expression and protein activity modulation.
Assuntos
Neoplasias , Survivina , Humanos , Survivina/metabolismo , Survivina/genética , Neoplasias/metabolismo , Neoplasias/patologia , Neoplasias/tratamento farmacológico , Neoplasias/genética , Animais , Proteínas Inibidoras de Apoptose/metabolismo , Proteínas Inibidoras de Apoptose/genética , Apoptose , MicroRNAs/genética , MicroRNAs/metabolismoRESUMO
Chemotherapeutic agents for treating colorectal cancer (CRC) primarily induce apoptosis in tumor cells. The ubiquitin-proteasome system is critical for apoptosis regulation. Deubiquitinating enzymes (DUBs) remove ubiquitin from substrates to reverse ubiquitination. Although over 100 DUB members have been discovered, the biological functions of only a small proportion of DUBs have been characterized. Here, we aimed to systematically identify the DUBs that contribute to the development of CRC. Among the DUBs, ubiquitin-specific protease 36 (USP36) is upregulated in CRC. We showed that the knockdown of USP36 induces intrinsic and extrinsic apoptosis. Through gene silencing and coimmunoprecipitation techniques, we identified survivin and cIAP1 as USP36 targets. Mechanistically, USP36 binds and removes lysine-11-linked ubiquitin chains from cIAP1 and lysine-48-linked ubiquitin chains from survivin to abolish protein degradation. Overexpression of USP36 disrupts the formation of the XIAP-second mitochondria-derived activator of caspase complex and promotes receptor-interacting protein kinase 1 ubiquitination, validating USP36 as an inhibitor to intrinsic and extrinsic apoptosis through deubiquitinating survivin and cIAP1. Therefore, our results suggest that USP36 is involved in CRC progression and is a potential therapeutic target.
Assuntos
Apoptose , Neoplasias Colorretais , Proteínas Inibidoras de Apoptose , Survivina , Ubiquitina Tiolesterase , Ubiquitinação , Humanos , Linhagem Celular Tumoral , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Neoplasias Colorretais/genética , Regulação Neoplásica da Expressão Gênica , Proteínas Inibidoras de Apoptose/metabolismo , Proteínas Inibidoras de Apoptose/genética , Survivina/metabolismo , Survivina/genética , Ubiquitina Tiolesterase/metabolismo , Ubiquitina Tiolesterase/genéticaRESUMO
Second mitochondrial-derived activator of caspase (SMAC), also known as direct inhibitor of apoptosis-binding proteins with low pI (Diablo), is known as a pro-apoptotic mitochondrial protein released into the cytosol in response to apoptotic signals. We recently reported SMAC overexpression in cancers as essential for cell proliferation and tumor growth due to non-apoptotic functions, including phospholipid synthesis regulation. These functions may be associated with its interactions with partner proteins. Using a peptide array with 768 peptides derived from 11 selected SMAC-interacting proteins, we identified SMAC-interacting sequences. These SMAC-binding sequences were produced as cell-penetrating peptides targeted to the cytosol, mitochondria, or nucleus, inhibiting cell proliferation and inducing apoptosis in several cell lines. For in vivo study, a survivin/baculoviral inhibitor of apoptosis repeat-containing 5 (BIRC5)-derived peptide was selected, due to its overexpression in many cancers and its involvement in mitosis, apoptosis, autophagy, cell proliferation, inflammation, and immune responses, as a target for cancer therapy. Specifically, a SMAC-targeting survivin/BIRC5-derived peptide, given intratumorally or intravenously, strongly inhibited lung tumor growth, cell proliferation, angiogenesis, and inflammation, induced apoptosis, and remodeled the tumor microenvironment. The peptide promoted tumor infiltration of CD-8+ cells and increased cell-intrinsic programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1) expression, resulting in cancer cell self-destruction and increased tumor cell death, preserving immune cells. Thus, targeting the interaction between the multifunctional proteins SMAC and survivin represents an innovative therapeutic cancer paradigm.
Assuntos
Proteínas Reguladoras de Apoptose , Apoptose , Proliferação de Células , Proteínas Mitocondriais , Survivina , Humanos , Survivina/metabolismo , Survivina/genética , Animais , Camundongos , Proteínas Mitocondriais/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Proteínas Reguladoras de Apoptose/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neoplasias/metabolismo , Neoplasias/patologia , Neoplasias/tratamento farmacológico , Inflamação/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Ligação Proteica , Proteínas Inibidoras de Apoptose/metabolismo , Proteínas Inibidoras de Apoptose/genética , Peptídeos Penetradores de Células/farmacologia , Peptídeos Penetradores de Células/química , Peptídeos/farmacologia , Peptídeos/química , Terapia de ImunossupressãoRESUMO
Lung adenocarcinoma (LUAD) is a subtype of lung cancer with high incidence and mortality globally. Emerging evidence suggests that circular RNAs (circRNAs) exert critical functions in human cancers, including LUAD. CircRNA_100549 (circ_100549) has been reported to be significantly upregulated in non-small cell lung cancer (NSCLC) samples, while its role in modulating LUAD progression remains to be explored. The current study aims at investigating the functional roles of circ_100549 in LUAD and its downstream molecular mechanism. First, we found that the expression of circ_100549 was higher in LUAD cell lines. Loss-of-function assays verified that depletion of circ_100549 repressed LUAD cell proliferation but accelerated cell apoptosis. Furthermore, in vivo experiments demonstrated that silencing of circ_100549 suppressed tumor growth. Subsequently, based on database analysis, we carried out a series of experiments to explore the mechanisms and effects of circ_100549 underlying LUAD progression, including RNA-binding protein immunoprecipitation (RIP), RNA/DNA pull-down, luciferase reporter, and chromatin immunoprecipitation (ChIP) assays. The results indicated that circ_100549 serves as a ceRNA by sponging miR-95-5p to upregulate BPTF expression, thus upregulating BIRC6 expression at a transcriptional level in LUAD. In summary, our study demonstrated that circ_100549 facilitates LUAD progression by upregulating BIRC6 expression.
Assuntos
Adenocarcinoma de Pulmão , Proteínas Inibidoras de Apoptose , Neoplasias Pulmonares , RNA Circular , Regulação para Cima , Humanos , RNA Circular/genética , RNA Circular/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/genética , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/genética , Camundongos , Proteínas Inibidoras de Apoptose/metabolismo , Proteínas Inibidoras de Apoptose/genética , Proliferação de Células , Apoptose , Camundongos Nus , Animais , Progressão da Doença , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética , Camundongos Endogâmicos BALB CRESUMO
PURPOSE: Oral Squamous Cell Carcinoma (OSCC) is the 6th most common cancer worldwide. It is generally aggressive and closely associated with chemoresistance and poor survival. There is accumulating evidence for the involvement of inhibitors of apoptosis proteins (IAPs), including IAP1 and XIAP, in mediating chemotherapy resistance in OSCC. Various strategies for targeting IAPs have been designed and tested in recent years and several small molecule IAP inhibitors are in clinical trials as monotherapies as well as in combination with radiotherapy and chemotherapy. The purpose of this study was to evaluate and compare the efficacy and biological activity of three IAP inhibitors both as stand-alone and sensitising agents to cisplatin in a preclinical model of squamous cell carcinoma of the tongue. METHODS: Cisplatin-sensitive SCC4 and -resistant SCC4cisR cells were utilised in this study. Apoptosis was evaluated by flow cytometric analysis of Annexin V/Propidium Iodide-stained cells. Expression of IAP proteins was determined by western blotting and knockdown of cIAP1, livin and XIAP was conducted by transfection of cells with siRNA. RESULTS: We establish for the first time the therapeutic efficacy of the Smac mimetic, BV6 and the XIAP inhibitor Embelin, for OSCC. Both of these IAP targeting agents synergistically enhanced cisplatin-mediated apoptotic cell death in resistant cells which was mediated in part by depletion of XIAP. In addition, knockdown of XIAP using siRNA enhanced cisplatin-mediated cell death, demonstrating the importance of targeting XIAP in this sensitisation. CONCLUSION: These findings provide pre-clinical evidence that IAP inhibition may be a valuable therapeutic option in OSCC.
Assuntos
Carcinoma de Células Escamosas , Neoplasias Bucais , Humanos , Cisplatino/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/genética , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo , Linhagem Celular Tumoral , Neoplasias Bucais/tratamento farmacológico , Proteínas Inibidoras de Apoptose/genética , Proteínas Inibidoras de Apoptose/metabolismo , Apoptose/fisiologia , Proteínas de Transporte , RNA Interferente PequenoRESUMO
Upregulation of the multidrug efflux pump ABCB1/MDR1 (P-gp) and the anti-apoptotic protein BIRC5/Survivin promotes multidrug resistance in various human cancers. GDC-0152 is a DIABLO/SMAC mimetic currently being tested in patients with solid tumors. However, it is still unclear whether GDC-0152 is therapeutically applicable for patients with ABCB1-overexpressing multidrug-resistant tumors, and the molecular mechanism of action of GDC-0152 in cancer cells is still incompletely understood. In this study, we found that the potency of GDC-0152 is unaffected by the expression of ABCB1 in cancer cells. Interestingly, through in silico and in vitro analysis, we discovered that GDC-0152 directly modulates the ABCB1-ATPase activity and inhibits ABCB1 multidrug efflux activity at sub-cytotoxic concentrations (i.e., 0.25×IC50 or less). Further investigation revealed that GDC-0152 also decreases BIRC5 expression, induces mitophagy, and lowers intracellular ATP levels in cancer cells at low cytotoxic concentrations (i.e., 0.5×IC50). Co-treatment with GDC-0152 restored the sensitivity to the known ABCB1 substrates, including paclitaxel, vincristine, and YM155 in ABCB1-expressing multidrug-resistant cancer cells, and it also restored the sensitivity to tamoxifen in BIRC5-overexpressing tamoxifen-resistant breast cancer cells in vitro. Moreover, co-treatment with GDC-0152 restored and potentiated the anticancer effects of paclitaxel in ABCB1 and BIRC5 co-expressing xenograft tumors in vivo. In conclusion, GDC-0152 has the potential for use in the management of cancer patients with ABCB1 and BIRC5-related drug resistance. The findings of our study provide essential information to physicians for designing a more patient-specific GDC-0152 clinical trial program in the future.
Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP , Benzodioxóis , Resistencia a Medicamentos Antineoplásicos , Indolizinas , Survivina , Humanos , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Survivina/genética , Survivina/metabolismo , Animais , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Camundongos Nus , Camundongos , Antineoplásicos/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas Reguladoras de Apoptose/metabolismo , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Paclitaxel/farmacologia , Proteínas Mitocondriais/metabolismo , Proteínas Mitocondriais/genética , Camundongos Endogâmicos BALB C , Proteínas Inibidoras de Apoptose/metabolismo , Proteínas Inibidoras de Apoptose/genéticaRESUMO
BACKGROUND: Metabolic reprogramming and abnormal glucose metabolism are hallmarks of head and neck squamous cell carcinoma (HNSCC). Certain oncogenes can promote cancer-related metabolic changes, but understanding their crosstalk in HNSCC biology and treatment is essential for identifying predictive biomarkers and developing target therapies. METHODS: We assessed the value of survivin/BIRC5 as a radioresistance factor potentially modulated by glucose for predicting therapeutic sensitivity and prognosis of HNSCC in a cohort of 32 patients. Additionally, we conducted in vitro experiments to explore the role of survivin/BIRC5 in glucose metabolism concerning radiation response. RESULTS: Tumoral BIRC5 expression is associated with serum glucose and predicts locoregional disease-free survival and lower BIRC5 mRNA levels are associated with better outcomes. Upregulation of BIRC5 by radiation depends on glucose levels and provokes a pro-tumoral and radioresistant phenotype in surviving cells. CONCLUSIONS: Survivin/BIRC5 might be independently associated with the risk of recurrence in patients with HNSCC.
Assuntos
Glucose , Neoplasias de Cabeça e Pescoço , Tolerância a Radiação , Carcinoma de Células Escamosas de Cabeça e Pescoço , Survivina , Humanos , Survivina/metabolismo , Survivina/genética , Masculino , Tolerância a Radiação/genética , Neoplasias de Cabeça e Pescoço/radioterapia , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/genética , Feminino , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Pessoa de Meia-Idade , Idoso , Glucose/metabolismo , Prognóstico , Linhagem Celular Tumoral , Intervalo Livre de Doença , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/radioterapia , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/genética , Proteínas Inibidoras de Apoptose/metabolismo , Proteínas Inibidoras de Apoptose/genética , AdultoRESUMO
Head and neck squamous cell carcinoma (HNSCC) ranks as the eighth most prevalent malignancy globally and has the eighth greatest fatality rate when compared to all other forms of cancer. The inhibitor of apoptosis protein (IAP) family comprises a collection of apoptosis-negative modulators characterized by at least one single baculovirus IAP repeat (BIR) domain in its N-terminal region. While the involvement of the IAP family is associated with the initiation and progression of numerous tumours, its specific role in HNSCC remains poorly understood. Thus, this study aimed to comprehensively examine changes in gene expression, immunomodulatory effects, prognosis, and functional enrichment of HNSCC utilising bioinformatics analysis. Elevated levels of distinct IAP family members were observed to varying degrees in HNSCC, with high BIRC2 expression indicating a worse prognosis. Additionally, Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to probe the enrichment of gene expression and biological processes related to the IAP family in HNSCC. The infiltration levels of immune cells were shown to be strongly associated with the IAP gene expression, as determined by subsequent analysis. Hence, BIRC2 could be an effective immunotherapy target for HNSCC. Collectively, novel knowledge of the biological roles and prognostic implications of IAP family members in HNSCC is presented in this study.
Assuntos
Neoplasias de Cabeça e Pescoço , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Prognóstico , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/terapia , Biomarcadores Tumorais/genética , Proteínas Inibidoras de Apoptose/genética , Regulação Neoplásica da Expressão GênicaRESUMO
Survivin holds significant importance as a member of the inhibitor of apoptosis protein (IAP) family due to its predominant expression in tumours rather than normal terminally differentiated adult tissues. The high expression level of survivin in tumours is closely linked to chemotherapy resistance, heightened tumour recurrence, and increased tumour aggressiveness and serves as a negative prognostic factor for cancer patients. Consequently, survivin has emerged as a promising therapeutic target for cancer treatment. In this review, we delve into the various biological characteristics of survivin in cancers and its pivotal role in maintaining immune system homeostasis. Additionally, we explore different therapeutic strategies aimed at targeting survivin.
Assuntos
Neoplasias , Adulto , Humanos , Survivina/uso terapêutico , Neoplasias/tratamento farmacológico , Proteínas Inibidoras de Apoptose/genética , Proteínas Inibidoras de Apoptose/metabolismo , Proteínas Inibidoras de Apoptose/uso terapêutico , Apoptose , Proteínas Associadas aos Microtúbulos/fisiologia , Proteínas Associadas aos Microtúbulos/uso terapêuticoRESUMO
Procaspase 9 is the initiator caspase for apoptosis, but how its levels and activities are maintained remains unclear. The gigantic Inhibitor-of-Apoptosis Protein BIRC6/BRUCE/Apollon inhibits both apoptosis and autophagy by promoting ubiquitylation of proapoptotic factors and the key autophagic protein LC3, respectively. Here we show that BIRC6 forms an anti-parallel U-shaped dimer with multiple previously unannotated domains, including a ubiquitin-like domain, and the proapoptotic factor Smac/DIABLO binds BIRC6 in the central cavity. Notably, Smac outcompetes the effector caspase 3 and the pro-apoptotic protease HtrA2, but not procaspase 9, for binding BIRC6 in cells. BIRC6 also binds LC3 through its LC3-interacting region, probably following dimer disruption of this BIRC6 region. Mutation at LC3 ubiquitylation site promotes autophagy and autophagic degradation of BIRC6. Moreover, induction of autophagy promotes autophagic degradation of BIRC6 and caspase 9, but not of other effector caspases. These results are important to understand how the balance between apoptosis and autophagy is regulated under pathophysiological conditions.
Assuntos
Apoptose , Proteínas Inibidoras de Apoptose , Apoptose/genética , Proteínas Inibidoras de Apoptose/genética , Proteínas Inibidoras de Apoptose/metabolismo , Caspases/metabolismo , Autofagia/genética , Ubiquitinação , Proteínas Mitocondriais/metabolismoRESUMO
O uso/dependência de álcool é importante fator de risco para o desenvolvimento da cirrose. O objetivo deste artigo é descrever e analisar o DALY (Disability Adjusted Life Years), o YLL (Years of Life Lost) e o YLD (Years Lived with Disability) de uso/dependência de álcool e da cirrose de etiologia não viral no Brasil, em 2008. O DALY foi calculado pela soma do YLL e do YLD. Para o YLL, foi utilizada a média dos óbitos de 2007-2009 no país. Através da revisão de dados epidemiológicos e do uso da ferramenta DisMod, a prevalência de cada um dos agravos foi modelada, gerando dados de incidência para o cálculo do YLD. O álcool e a cirrose foram responsáveis, respectivamente, por 3% e 1% do DALY total. Considerando-se as dez primeiras causas de DALY para homens, o uso/ dependência de álcool ocupou a segunda, terceira e sexta posições nas idades de 15-29, 30-44 e 45-59 anos, respectivamente. A cirrose ocupou a oitava posição no grupo de 30-44 anos; a quinta, no de 45-59 e a oitava, no de 60-69. A distribuição dos agravos por faixa etária sugere que intervenções direcionadas ao uso/dependência de álcool terão efeitos na carga de cirrose alcoólica no país.
Alcohol use/dependence are an important risk factor for cirrhosis of the liver. The article aims to describe and conduct a comparative analysis of Disability Adjusted Life Years (DALY), Years of Life Lost (YLL) and Years Lived with Disability (YLD) of alcohol use disorders and non-viral cirrhosis in Brazil in 2008. DALY was calculated as the sum of YLL and YLD. For YLL estimates, the mean number of deaths from 2007- 2009 in the country was considered. After revision of epidemiological data, prevalence of each disease was modelled with the DisMod tool, which generated incidence data for YLD estimates. Alcohol and non-viral cirrhosis were responsible for 3% and 1% of total DALYs, respectively. In both diseases, men contributed to a greater proportion of DALYs. Among the first ten causes of DALYs, alcohol use disorders occupied the second, third and sixth positions at the ages of 15-29, 30-44 and 45- 59, respectively. Non-viral cirrhosis was the eighth cause of DALY in the 30-44 age group in men; the fifth, in the 45-59 group and the eighth, in the 60-69 group. Age distribution suggests that interventions directed against alcohol use/dependence would have effects on the burden of alcoholic cirrhosis in the country.
Assuntos
Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Biomarcadores Tumorais/genética , Colo/metabolismo , Neoplasias do Colo/genética , Proteínas Inibidoras de Apoptose/genética , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/secundário , Adenoma/genética , Adenoma/metabolismo , Adenoma/patologia , Apoptose , Biomarcadores Tumorais/metabolismo , Estudos de Casos e Controles , Estudos de Coortes , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Seguimentos , Perfilação da Expressão Gênica , Técnicas Imunoenzimáticas , Proteínas Inibidoras de Apoptose/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Metástase Linfática , Estadiamento de Neoplasias , Análise de Sequência com Séries de Oligonucleotídeos , Estudos Prospectivos , RNA Mensageiro/genética , Estudos Retrospectivos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Taxa de Sobrevida , Resultado do TratamentoRESUMO
Neuroblastoma is a solid tumor that occurs mainly in children. Malignant neuroblastomas have a poor prognosis because conventional chemotherapeutic agents are not very effective. Survivin, a member of the inhibitor of the apoptosis protein family, plays a significant role in cell division, inhibition of apoptosis, and promotion of cell proliferation and invasion. Previous studies found that survivin is highly expressed in some malignant neuroblastomas and is correlated with poor prognosis. The aim of this study was to investigate whether survivin could serve as a potential therapeutic target of human neuroblastoma. We employed RNA interference to reduce survivin expression in the human neuroblastoma SH-SY5Y cell line and analyzed the effect of RNA interference on cell proliferation and invasion in vitro and in vivo. RNA interference of survivin led to a significant decrease in invasiveness and proliferation and increased apoptosis in SH-SY5Y cells in vitro. RNA interference of survivin inhibited tumor growth in vivo by 68±13% (P=0.002) and increased the number of apoptotic cells by 9.8±1.2% (P=0.001) compared with negative small interfering RNA (siRNA) treatment controls. Moreover, RNA interference of survivin inhibited the formation of lung metastases by 92% (P=0.002) and reduced microvascular density by 60% (P=0.0003). Survivin siRNA resulted in significant downregulation of survivin mRNA and protein expression both in vitro and in vivo compared with negative siRNA treatment controls. RNA interference of survivin was found to be a potent inhibitor of SH-SY5Y tumor growth and metastasis formation. These results support further clinical development of RNA interference of survivin as a treatment of neuroblastoma and other cancer types.
Assuntos
Animais , Humanos , Apoptose/efeitos dos fármacos , Inibidores de Cisteína Proteinase/farmacologia , Proteínas Inibidoras de Apoptose/efeitos dos fármacos , Neoplasias Pulmonares/secundário , Neuroblastoma/patologia , RNA Interferente Pequeno/farmacologia , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Proteínas Inibidoras de Apoptose/genética , Proteínas Inibidoras de Apoptose/metabolismo , Camundongos Nus , Invasividade Neoplásica , Neuroblastoma/secundário , Reação em Cadeia da Polimerase Via Transcriptase Reversa , RNA Neoplásico/efeitos dos fármacos , RNA Neoplásico/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Cisplatin resistance remains one of the major obstacles when treating epithelial ovarian cancer. Because oxaliplatin and nedaplatin are effective against cisplatin-resistant ovarian cancer in clinical trials and signal transducer and activator of transcription 3 (STAT3) is associated with cisplatin resistance, we investigated whether overcoming cisplatin resistance by oxaliplatin and nedaplatin was associated with the STAT3 pathway in ovarian cancer. Alamar blue, clonogenic, and wound healing assays, and Western blot analysis were used to compare the effects of platinum drugs in SKOV-3 cells. At an equitoxic dose, oxaliplatin and nedaplatin exhibited similar inhibitory effects on colony-forming ability and greater inhibition on cell motility than cisplatin in ovarian cancer. Early in the time course of drug administration, cisplatin increased the expression of pSTAT3 (Tyr705), STAT3α, VEGF, survivin, and Bcl-XL, while oxaliplatin and nedaplatin exhibited the opposite effects, and upregulated pSTAT3 (Ser727) and STAT3β. The STAT3 pathway responded early to platinum drugs associated with cisplatin resistance in epithelial ovarian cancer and provided a rationale for new therapeutic strategies to reverse cisplatin resistance.