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1.
Breast Cancer Res ; 21(1): 107, 2019 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-31533767

RESUMO

The introduction of next-generation sequencing has resulted in testing multiple genes simultaneously to identify inherited pathogenic variants (PVs) in cancer susceptibility genes. PVs with low minor allele frequencies (MAFs) (< 25-35%) are highlighted on germline genetic test reports. In this review, we focus on the challenges of interpreting PVs with low MAF in breast cancer patients undergoing germline testing and the implications for management.The clinical implications of a germline PV are substantial. For PV carriers in high-penetrance genes like BRCA1, BRCA2, and TP53, prophylactic mastectomy is often recommended and radiation therapy avoided when possible for those with Li-Fraumeni syndrome (LFS). For germline PV carriers in more moderate-risk genes such as PALB2, ATM, and CHEK2, annual breast MRI is recommended and prophylactic mastectomies considered for those with significant family histories. Detection of PVs in cancer susceptibility genes can also lead to recommendations for other prophylactic surgeries (e.g., salpingo-oophorectomy) and increased surveillance for other cancers. Therefore, recognizing when a PV is somatic rather than germline and distinguishing somatic mosaicism from clonal hematopoiesis (CH) is essential. Mutational events that occur at a post-zygotic stage are somatic and will only be present in tissues derived from the mutated cell, characterizing classic mosaicism. Clonal hematopoiesis is a form of mosaicism restricted to the hematopoietic compartment.Among the genes in multi-gene panels used for germline testing of breast cancer patients, the detection of a PV with low MAF occurs most often in TP53, though has been reported in other breast cancer susceptibility genes. Distinguishing a germline TP53 PV (LFS) from a somatic PV (TP53 mosaicism or CH) has enormous implications for breast cancer patients and their relatives.We review how to evaluate a PV with low MAF. The identification of the PV in another tissue confirms mosaicism. Older age, exposure to chemotherapy, radiation, and tobacco are known risk factors for CH, as is the absence of a LFS-related cancer in the setting of a TP53 PV with low MAF. The ability to recognize and understand the implications of somatic PVs, including somatic mosaicism and CH, enables optimal personalized care of breast cancer patients.


Assuntos
Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Síndrome de Li-Fraumeni/diagnóstico , Síndrome de Li-Fraumeni/genética , Diagnóstico Diferencial , Frequência do Gene , Genes p53/genética , Testes Genéticos , Hematopoese , Humanos , Mosaicismo , Mutação
2.
Pathologe ; 40(6): 592-599, 2019 Nov.
Artigo em Alemão | MEDLINE | ID: mdl-31511974

RESUMO

The Li-Fraumeni syndrome (LFS, online Mendelian inheritance in man, OMIM #151623) is considered to be one of the currently known most aggressive cancer predisposition syndromes. The heterogeneous spectrum of tumors is dominated by bone and soft tissue sarcomas, various brain tumors, premenopausal breast cancer and adrenocortical carcinoma (ACC). Even in childhood the cancer risk is very strongly increased and it is not uncommon for people with LFS to develop synchronous and metachronous tumors. Typical histopathological findings and molecular genetic signatures can help towards the diagnosis. Inheritance is autosomal dominant and the penetrance appears to be more variable than previously thought. The prevalence of LFS is approximately 1:5000 with a high interregional variance. The LFS is caused by germline mutations in the TP53 gene coding for the protein p53, an essential cellular transcription factor that initiates antitumor responses to cellular stress, such as DNA damage. In people with LFS, due to the loss of functional p53, the protective mechanism of the cells is weakened resulting in a significantly increased cancer risk. In order to improve the survival of people with LFS, structured tumor early recognition and surveillance strategies are recommended; however, national and international longitudinal observational studies are needed to evaluate the cost-effort-benefit balance. For this reason, the authors have established the LFS cancer predisposition registry in which all patients with LFS and other syndromes predisposing to cancer can be registered. Detailed information can be found at www.cancer-predisposition.org .


Assuntos
Predisposição Genética para Doença , Síndrome de Li-Fraumeni , Genes p53/genética , Humanos , Síndrome de Li-Fraumeni/genética , Síndrome de Li-Fraumeni/mortalidade , Síndrome de Li-Fraumeni/patologia
3.
Prostate ; 79(12): 1362-1377, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31269242

RESUMO

BACKGROUND: Prostate cancer (PCa) is one of the most common cancers in males in China. Long noncoding RNAs (lncRNAs) reportedly play crucial roles in human cancer progression in many studies. However, the molecular mechanisms underlying PCa progression remain unclear. MATERIALS AND METHODS: We investigated the lncRNA transcriptome using publicly available RNA-sequencing data to identify prostate-specific lncRNAs. Then, the chromatin immunoprecipitation (ChIP) assay identified lncRNA with a direct binding to androgen receptor (AR), hereafter denoted as PSLNR. Quantitative real-time polymerase chain reaction analysis and Western blot analysis were performed to detect the expression of p53 signaling-related genes after overexpression PSLNR. The effects of overexpression of PSLNR on cell proliferation, cell cycle, and cell apoptosis were assessed by using CCK-8 and flow cytometric analysis. We then detected the expression of PSLNR in tissues. RESULT: We reported a novel androgen-reduced prostate-specific lncRNA, PSLNR, that inhibited PCa progression via the p53-dependent pathway. By analyzing the NOCODE data set, we reported that PSLNR was specifically expressed in the prostate, suggesting the potential of PSLNR as a biomarker for PCa treatment. The AR pathway was also confirmed to be an upstream regulation signaling pathway of PSLNR by transcriptionally regulating its expression in androgen-dependent PCa cells. PSLNR also significantly inhibited PCa proliferation by inducing cell apoptosis in a p53-dependent manner. Thus, PSLNR may be a candidate diagnosis and therapeutic target for PCa. CONCLUSIONS: Our study revealed for the first time a novel androgen-reduced prostate-specific lncRNA, PSLNR, which inhibited PCa progression via the p53-dependent pathway, suggesting that PSLNR may be a candidate diagnosis and therapeutic target for PCa.


Assuntos
Biomarcadores Tumorais/genética , Genes p53/genética , Próstata/metabolismo , Neoplasias da Próstata/genética , RNA Longo não Codificante/genética , Receptores Androgênicos/metabolismo , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Progressão da Doença , Genes p53/fisiologia , Humanos , Masculino , Neoplasias da Próstata/metabolismo , RNA Longo não Codificante/biossíntese , Transdução de Sinais
4.
Am J Vet Res ; 80(7): 680-688, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31246118

RESUMO

OBJECTIVE: To examine effects of a common mutation (2-base insertion in exon 5) of the TP53 gene on biological function of p53 protein in canine histiocytic sarcoma cells. SAMPLE: Canine histiocytic tumor cell lines DH82 with deletion of TP53 and CHS-3 with the wild-type TP53 and canine wild-type and mutant TP53 fragments. PROCEDURES: Wild-type or mutant TP53 with a polyprotein peptide tag at the N-terminus was transduced into DH82 and CHS-3 cells. Expression of p53 protein, changes in function as a transcription factor, and susceptibility to doxorubicin and nimustine were compared. RESULTS: Transduced p53 protein was detected in wild-type TP53-transduced DH82 and CHS-3 cells, whereas expression was not detected in mutant TP53-transduced cells. There were significant increases in expression of target genes of p53 protein, including p21 and MDM2, in wild-type TP53-transduced cells, compared with results for native and mock-transfected cells, but not in mutant TP53-transduced cells. There was no significant difference in drug susceptibilities among native and derivative cells of CHS-3. However, cell viabilities of wild-type TP53-transduced DH82 cells incubated with doxorubicin were significantly lower than viabilities of native, mock-transfected, and AT insertion mutation-TP53-transduced DH82 cells; susceptibility to nimustine did not differ significantly among cells. CONCLUSIONS AND CLINICAL RELEVANCE: Expression of p53 protein and its function as a transcription factor were lost after addition of a 2-base insertion in the TP53 gene in canine histiocytic tumor cells. Additional studies are needed to investigate the clinical relevance of this mutation in histiocytic sarcomas of dogs.


Assuntos
Cães , Mutagênese Insercional/fisiologia , Proteína Supressora de Tumor p53/genética , Animais , Linhagem Celular Tumoral , Doenças do Cão/fisiopatologia , Genes p53/genética , Sarcoma Histiocítico/fisiopatologia , Sarcoma Histiocítico/veterinária , Mutação , Proteína Supressora de Tumor p53/metabolismo
6.
Pediatr Int ; 61(8): 759-767, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31211452

RESUMO

BACKGROUND: While leukocyte telomere length has been linked with altered risk in adult cancer, limited information is available on its association with risk in pediatric solid tumors. We investigated the association of telomeric alterations with risk of pediatric solid tumors. We also investigated whether altered telomeres cooperated with the TP53 rs1042522, MDM2 rs2279744 and CDKN1A (p21cip1 ) rs1059234 single-nucleotide polymorphisms to modify cancer risk. METHODS: A total of 101 tumor patients and 202 controls were recruited for this age- and gender-matched case-control study. Relative telomere length (RTL) was determined in peripheral blood leukocytes using quantitative real-time polymerase chain reaction (PCR), and the polymorphisms were genotyped using PCR-restriction fragment length polymorphism. RESULTS: Using median RTL in the healthy controls as a cut-off, children with longer telomeres were at an increased risk of developing a solid tumor (OR, 2.70; P < 0.01). When participants were categorized according to control RTL quartiles, a significant dose-response relationship was observed (χ2  = 10.95; P < 0.001). The risk for tumors increased nearly threefold (P = 0.001) for the triple interaction RTL × TP53 rs1042522 × p21cip1 rs1059234 compared with the maximum effect of any single factor, although the interaction effect was less than additive. The MDM2 rs2279744 GG genotype reduced pediatric solid tumor risk significantly (OR, 0.51). CONCLUSION: Combined analysis of telomeres and genetic polymorphisms in the TP53 pathway can provide important clues to understanding pediatric solid tumor etiology.


Assuntos
Biomarcadores Tumorais/genética , Inibidor de Quinase Dependente de Ciclina p21/genética , Genes p53/genética , Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas c-mdm2/genética , Homeostase do Telômero , Adolescente , Análise do Polimorfismo de Comprimento de Fragmentos Amplificados , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Predisposição Genética para Doença , Humanos , Lactente , Recém-Nascido , Masculino , Neoplasias/diagnóstico , Reação em Cadeia da Polimerase em Tempo Real , Medição de Risco , Sensibilidade e Especificidade
7.
Int J Cancer ; 145(9): 2535-2546, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31241175

RESUMO

Despite its anticipated clinical potential, anti-PD-1 immunotherapy has only yielded poor outcomes in recent clinical trials for glioblastoma patients. Strategies combining anti-PD-1 antibody with other treatment modalities are being explored to alter the immunosuppressive microenvironment that appears to characterize these anti-PD-1-insensitive tumors. Here, we evaluated whether introducing wild-type p53 gene via a tumor-targeting nanomedicine (termed SGT-53) could provide immune stimulation and augment anti-PD-1 therapy in mouse syngeneic GL261 tumor models (either subcutaneous or intracranial). In both models, anti-PD-1 monotherapy had no demonstrable therapeutic effect. However, combining anti-PD-1 with our investigational nanomedicine SGT-53 was very effective in inhibiting tumor growth, inducing tumor cell apoptosis and increasing intratumoral T-cell infiltration. A significant survival benefit was observed in mice bearing intracranial glioblastoma receiving combination treatment. Importantly, SGT-53 upregulated PD-L1 expression both in vitro and in vivo. Transcriptome analysis revealed modulation of genes linked to either cancer progression or immune activation after combination treatment. Our data suggest that SGT-53 can boost antitumor immunity and sensitize glioblastoma to anti-PD-1 therapy by converting immunologically "cold" tumors into "hot" tumors. Combining SGT-53 with anti-PD-1 might benefit more patients from anti-PD-1 immunotherapy and our data support evaluation of this combination in patients with glioblastoma.


Assuntos
Barreira Hematoencefálica/metabolismo , Genes p53/genética , Glioblastoma/genética , Receptor de Morte Celular Programada 1/metabolismo , Proteína Supressora de Tumor p53/genética , Animais , Apoptose/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Terapia Combinada/métodos , Modelos Animais de Doenças , Progressão da Doença , Feminino , Glioblastoma/tratamento farmacológico , Glioblastoma/imunologia , Glioblastoma/terapia , Imunoterapia/métodos , Camundongos , Camundongos Endogâmicos C57BL , Nanomedicina/métodos , Células RAW 264.7 , Linfócitos T/patologia , Transcriptoma/genética , Microambiente Tumoral/genética , Regulação para Cima/genética , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
10.
Elife ; 82019 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-31090541

RESUMO

While lower vertebrates contain adult stem cells (aSCs) that maintain homeostasis and drive un-exhaustive organismal growth, mammalian aSCs display mainly the homeostatic function. Here, we use lineage analysis in the medaka fish gill to address aSCs and report separate stem cell populations for homeostasis and growth. These aSCs are fate-restricted during the entire post-embryonic life and even during re-generation paradigms. We use chimeric animals to demonstrate that p53 mediates growth coordination among fate-restricted aSCs, suggesting a hierarchical organisation among lineages in composite organs like the fish gill. Homeostatic and growth aSCs are clonal but differ in their topology; modifications in tissue architecture can convert the homeostatic zone into a growth zone, indicating a leading role for the physical niche defining stem cell output. We hypothesise that physical niches are main players to restrict aSCs to a homeostatic function in animals with fixed adult size.


Assuntos
Tecido Adiposo/crescimento & desenvolvimento , Células-Tronco Adultas/metabolismo , Brânquias/crescimento & desenvolvimento , Oryzias/crescimento & desenvolvimento , Tecido Adiposo/metabolismo , Animais , Diferenciação Celular/genética , Quimera/genética , Quimera/crescimento & desenvolvimento , Genes p53/genética , Brânquias/metabolismo , Homeostase/genética , Humanos , Oryzias/metabolismo , Nicho de Células-Tronco/genética
12.
Mol Biol Rep ; 46(3): 2885-2891, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30859450

RESUMO

Repeated implantation failure (RIF) is one the most common causes which showed during IVF (In vitro fertilization) procedure. We aim to evaluate the possibility role of nucleotide changes in rs1042522 (R72P; G/C) and rs17878362 (Ins16bp; N/D) of P53 gene in patients with RIF. In a case-control survey, we have considered 200 women, consisting of 100 cases with RIF and 100 women with the normal pregnancy. In order to determine the genotype frequencies, we used polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The NN + ND/DD (dominant) genotype frequencies of rs17878362 variant revealed a significant difference between two groups (P = 0.001; OR 2.652; 95% CI 1.480-4.754). In addition, the CC + GC/GG (recessive) genotype frequencies of rs1042522 (R72P) variant indicated a significant difference between two groups (P = 0.018; OR 3.353; 95% CI 1.169-9.616). Our findings suggested that rs1042522 (R72P; G/C) and rs17878362 (Ins16bp; N/D) of P53 gene polymorphisms could be a genetic predisposing factor for RIF.


Assuntos
Implantação do Embrião/genética , Genes p53/genética , Genes p53/fisiologia , Aborto Espontâneo/genética , Adulto , Alelos , Estudos de Casos e Controles , Implantação do Embrião/fisiologia , Feminino , Fertilização In Vitro/métodos , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único/genética , Gravidez , Proteína Supressora de Tumor p53/genética
15.
BMC Cancer ; 19(1): 118, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30709381

RESUMO

BACKGROUND: Heterozygous germline TP53 gene mutations result in Li-Fraumeni Syndrome (LFS). Breast cancer (BC) is the most frequent tumor in young women with LFS. An important issue related to BC in the Mexican population is the average age at diagnosis, which is approximately 11 years younger than that of patients in the United States (U.S.) and Europe. The aim of this study was to determine the prevalence of germline mutations in TP53 among young Mexican BC patients. METHODS: We searched for germline mutations in the TP53 gene using targeted next-generation sequencing (NGS) in 78 BC patients younger than 45 years old (yo) who tested negative for BRCA1/2 mutations. A group of 509 Mexican women aged 45yo or older without personal or family BC history (parents/grandparents) was used as a control. RESULTS: We identified five patients with pathogenic variants in the TP53 gene, equivalent to 6.4% (5/78). Among patients diagnosed at age 36 or younger, 9.4% (5/55) had pathogenic TP53 mutations. Three of these variants were missense mutations (c.844C > T, c.517G > A, and c.604C > T), and the other two mutations were frameshifts (c.291delC and c.273dupC) and had not been reported previously. We also identified a variant of uncertain clinical significance (VUS), c.672G > A, which causes a putative splice donor site mutation. All patients with TP53 mutations had high-grade and HER2-positive tumors. None of the 509 patients in the healthy control group had mutations in TP53. CONCLUSIONS: Among Mexican BC patients diagnosed at a young age, we identified a high proportion with germline mutations in the TP53 gene. All patients with the TP53 mutations had a family history suggestive of LFS. To establish the clinical significance of the VUS found, additional studies are needed. Pathogenic variants of TP53 may explain a substantial fraction of BC in young women in the Mexican population. Importantly, none of these mutations or other pathological variants in TP53 were found in the healthy control group.


Assuntos
Neoplasias da Mama/genética , Genes p53/genética , Predisposição Genética para Doença/genética , Mutação em Linhagem Germinativa/genética , Adulto , Fatores Etários , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/patologia , Feminino , Estudos de Associação Genética , Variação Genética , Humanos , Síndrome de Li-Fraumeni/epidemiologia , Síndrome de Li-Fraumeni/genética , México/epidemiologia , Linhagem , Prevalência , Adulto Jovem
17.
Mod Pathol ; 32(3): 415-422, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30291345

RESUMO

The impact of TP53 gene mutations in recurrent HPV-negative vulvar squamous cell carcinomas is unclear. TP53 gene mutations were analyzed in archival tissues of 24 primary squamous cell carcinoma and local vulvar recurrences arising in chronic inflammatory dermatoses by analyzing the full coding sequence of the TP53 gene and correlated with disease-free survival. After resection of the primary squamous cell carcinoma with clear margins 19/24 patients had one and 5/24 had multiple recurrences. The first recurrence occurred after median of 46 months (range 12-180 months). In all, 17/24 (71%) primary squamous cell carcinomas had TP53 gene mutations and recurred after median disease-free intervals of 33 months (range 12-180). 14/17 (88%) recurrent squamous cell carcinomas carried again TP53 gene mutations, five with identical and nine with different, more complex TP53 gene mutations. 7/24 (29%) patients with a p53 wild-type primary SCC had the first recurrence after median 65 months (range 14-144) featuring p53 wild-type in 3/7 (43%) and TP53 gene mutations in 4/7 (57%) recurrent squamous cell carcinomas. Disease-free intervals of > 5 years (60-180 months) were observed in 10/24 patients total (42%; equally divided among p53 wild-type (5/7; 71%) and TP53 gene mutated (5/17; 29%) squamous cell carcinomas). In summary, squamous cell carcinomas recurred in the residual vulvar dermatosis independent of TP53 gene mutational status of the primary squamous cell carcinoma. The majority of TP53 gene mutated cancers recurred with different TP53 gene mutations, some of them more complex, and patients with p53 wild type developed TP53 gene mutations in the recurrent squamous cell carcinomas, possibly indicating increased genetic instability in longstanding chronic inflammatory dermatoses. A change of TP53 gene mutational status after > 5 years suggests de novo oncogenic events/carcinogenesis. Longer disease-free intervals in patients with p53 wild-type primary squamous cell carcinoma suggest that TP53 gene mutational status may serve as a prognostic marker for disease-free intervals.


Assuntos
Carcinoma de Células Escamosas/genética , Recidiva Local de Neoplasia/genética , Proteína Supressora de Tumor p53/genética , Neoplasias Vulvares/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/patologia , Feminino , Genes p53/genética , Humanos , Pessoa de Meia-Idade , Mutação , Recidiva Local de Neoplasia/patologia , Neoplasias Vulvares/patologia
18.
Hum Mol Genet ; 28(3): 434-447, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30304535

RESUMO

Building a cerebral cortex of the proper size involves balancing rates and timing of neural stem cell (NSC) proliferation, neurogenesis and cell death. The cellular mechanisms connecting genetic mutations to brain malformation phenotypes are still poorly understood. Microcephaly may result when NSC divisions are too slow, produce neurons too early or undergo apoptosis but the relative contributions of these cellular mechanisms to various types of microcephaly are not understood. We previously showed that mouse mutants in Kif20b (formerly called Mphosph1, Mpp1 or KRMP1) have small cortices that show elevated apoptosis and defects in maturation of NSC midbodies, which mediate cytokinetic abscission. Here we test the contribution of intrinsic NSC apoptosis to brain size reduction in this lethal microcephaly model. By making double mutants with the pro-apoptotic genes Bax and Trp53 (p53), we find that p53-dependent apoptosis of cortical NSCs accounts for most of the microcephaly, but that there is a significant apoptosis-independent contribution as well. Remarkably, heterozygous p53 deletion is sufficient to fully rescue survival of the Kif20b mutant into adulthood. In addition, the NSC midbody maturation defects are not rescued by p53 deletion, showing that they are either upstream of p53 activation, or in a parallel pathway. Accumulation of p53 in the nucleus of mutant NSCs at midbody stage suggests the possibility of a novel midbody-mediated pathway for p53 activation. This work elucidates both NSC apoptosis and abscission mechanisms that could underlie human microcephaly or other brain malformations.


Assuntos
Genes p53/genética , Microcefalia/genética , Células-Tronco Neurais/fisiologia , Animais , Apoptose/genética , Diferenciação Celular/genética , Proliferação de Células/genética , Células Cultivadas , Córtex Cerebral/metabolismo , Modelos Animais de Doenças , Genes p53/fisiologia , Cinesina/genética , Cinesina/fisiologia , Masculino , Camundongos , Microcefalia/fisiopatologia , Mutação , Neurogênese/genética , Neurônios/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/fisiologia
19.
Amino Acids ; 51(2): 311-318, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30377840

RESUMO

Anticancer peptides (ACPs) are biologically anticancer active molecules that are produced by mammals, plants, insects and microorganisms. Here, a new peptide (TC22) with the amino acid sequence MTVVLLLIVLPLLGGVHSSGIL was identified and characterized from the beetle Tribolium castaneum. We found it inhibited the growth and viability of HeLa and MCF-7 cells. Flow cytometry analysis demonstrated the TC22 induced HeLa cell apoptosis, and activated caspase-9 and caspase-3. Furthermore, TC22 led to ROS generation, and triggered p53 transcription and expression. Taken together, our results indicated that TC22 exhibited high anticancer capacity via activating p53, inducing ROS generation and through a mitochondrial pathway. This research provided a novel natural source peptide with strong anticancer capacity. These findings provide some novel insights on the potential candidate reagent in cancer treatment.


Assuntos
Anticarcinógenos/isolamento & purificação , Anticarcinógenos/farmacologia , Proteínas de Insetos/isolamento & purificação , Proteínas de Insetos/farmacologia , Peptídeos/isolamento & purificação , Peptídeos/farmacologia , Tribolium/química , Animais , Anticarcinógenos/uso terapêutico , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 9/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Expressão Gênica , Genes p53/genética , Células HeLa , Humanos , Proteínas de Insetos/uso terapêutico , Células MCF-7 , Peptídeos/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Transcrição Genética
20.
Genes Immun ; 20(7): 539-554, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30563970

RESUMO

Alterations in the molecular mechanisms of cell death are a common feature of cancer. These alterations enable malignant cells to survive intrinsic death signalling leading to accumulation of genetic aberrations and helping them to cope with adverse conditions. Regulated cell death has historically been exclusively associated with classical apoptosis; however, increasing evidence indicates that several alternative mechanisms orchestrate multiple death pathways, such as ferroptosis, entosis, necroptosis and immunogenic cell death, each with distinct underlying molecular mechanisms. Although pharmacological targeting of cell death pathways has been the subject of intensive efforts in recent decades with a dominant focus on targeting apoptosis, the identification of these novel death pathways has opened additional venues for intervention in cancer cells and the immune system. In this mini-review, we cover some recent progress on major recently emerged cell death modalities, emphasizing their potential clinical and therapeutic implications. We also discuss the interplay between cell death and immune response, highlighting the potential of the combination of traditional anticancer therapy and immunocheckpoint blockade. While attempting to stimulate discussion and draw attention to the possible clinical impact of these more recently emerged cell death modalities, we also cover the major progress achieved in translating strategies for manipulation of apoptotic pathways into the clinic, focusing on the attempts to target the anti-apoptotic protein BCL2 and the tumour suppressor p53.


Assuntos
Morte Celular/efeitos dos fármacos , Morte Celular/fisiologia , Neoplasias/terapia , Apoptose/genética , Entose , Genes bcl-2/genética , Genes p53/genética , Humanos , Sistema Imunitário , Imunoterapia , Neoplasias/genética , Transdução de Sinais
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