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1.
Leukemia ; 37(2): 441-452, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36446947

RESUMEN

DLBCL is the most common lymphoma with high tumor heterogeneity. Treatment refractoriness and relapse from R-CHOP therapy in patients remain a clinical problem. Activation of the non-canonical NF-κB pathway is associated with R-CHOP resistance. However, downstream targets of non-canonical NF-κB mediating R-CHOP-induced resistance remains uncharacterized. Here, we identify the common mechanisms underlying both intrinsic and acquired resistance that are induced by doxorubicin, the main cytotoxic component of R-CHOP. We performed global transcriptomic analysis of (1) a panel of resistant versus sensitive and (2) isogenic acquired doxorubicin-resistant DLBCL cell lines following short and chronic exposure to doxorubicin respectively. Doxorubicin-induced stress in resistant cells activates a distinct transcriptional signature that is enriched in metabolic reprogramming and oncogenic signalling. Selective and sustained activation of non-canonical NF-κB signalling in these resistant cells exacerbated their survival by augmenting glycolysis. In response to doxorubicin, p52-RelB complexes transcriptionally activated multiple glycolytic regulators with prognostic significance through increased recruitment at their gene promoters. Targeting p52-RelB and their targets in resistant cells increased doxorubicin sensitivity in vitro and in vivo. Collectively, our study uncovered novel molecular drivers of doxorubicin-induced resistance that are regulated by non-canonical NF-κB pathway. We reveal new avenues of therapeutic targeting for R-CHOP-treated refractory/relapsed DLBCL patients.


Asunto(s)
Antineoplásicos , Linfoma de Células B Grandes Difuso , Humanos , FN-kappa B/metabolismo , Recurrencia Local de Neoplasia/tratamiento farmacológico , Transducción de Señal , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Antineoplásicos/uso terapéutico , Rituximab/farmacología , Rituximab/uso terapéutico , Ciclofosfamida/uso terapéutico , Vincristina/farmacología , Vincristina/uso terapéutico , Prednisona/uso terapéutico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/patología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico
3.
Cell Rep ; 22(1): 299-312, 2018 01 02.
Artículo en Inglés | MEDLINE | ID: mdl-29298430

RESUMEN

The large number of mutations identified across all cancers represents an untapped reservoir of targets that can be useful for therapeutic targeting if highly selective, mutation-specific reagents are available. We report here our attempt to generate such reagents: monoclonal antibodies against the most common R175H, R248Q, and R273H hotspot mutants of the tumor suppressor p53. These antibodies recognize their intended specific alterations without any cross-reactivity against wild-type (WT) p53 or other p53 mutants, including at the same position (as exemplified by anti-R248Q antibody, which does not recognize the R248W mutation), evaluated by direct immunoblotting, immunoprecipitation, and immunofluorescence methods on transfected and endogenous proteins. Moreover, their clinical utility to diagnose the presence of specific p53 mutants in human tumor microarrays by immunohistochemistry is also shown. Together, the data demonstrate that antibodies against specific single-amino-acid alterations can be generated reproducibly and highlight their utility, which could potentially be extended to therapeutic settings.


Asunto(s)
Anticuerpos Monoclonales de Origen Murino/química , Especificidad de Anticuerpos , Mutación , Proteína p53 Supresora de Tumor/inmunología , Animales , Anticuerpos Monoclonales de Origen Murino/inmunología , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Medicina de Precisión , Proteína p53 Supresora de Tumor/química , Proteína p53 Supresora de Tumor/genética
4.
Sci Rep ; 6: 20299, 2016 Feb 02.
Artículo en Inglés | MEDLINE | ID: mdl-26831370

RESUMEN

The cumulative effects of hepatic injury due to hepatitis B virus (HBV) infections and aflatoxin-B1 (AFB1) exposure are the major risk factors of HCC. Understanding early metabolic changes involving these risk factors in an animal model closely resembling human hepatocellular carcinoma (HCC) is critical for biomarker discovery and disease therapeutics. We have used the hepatitis B surface antigen (HBsAg) transgenic mouse model that mimics HBV carriers with and without AFB1 treatment. We investigated early metabolic changes from preneoplastic state to HCC by non-invasive longitudinal imaging in three HCC groups of mice: HBsAg + AFB1(Gp-I), AFB1 alone (Gp-II), HBsAg alone (Gp-III) and a control group (wild-type untreated; Gp-IV). For the first time, we have identified acylcarnitine signals in vivo in the liver prior to the histological manifestation of the tumors in all three groups. Acylcarnitine concentration increased with increase in tumor growth in all HCC mouse models, indicating elevated metabolic activity and increased cell turnover. This was confirmed in a pilot study using human serum from HCC patients, which revealed a higher concentration of acylcarnitine compared with normal subjects. Translational clinical studies can be designed to detect acylcarnitine in patients with high risk factors for HCC.


Asunto(s)
Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/metabolismo , Carnitina/análogos & derivados , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/metabolismo , Imagen Molecular , Animales , Biomarcadores , Carcinoma Hepatocelular/genética , Carnitina/sangre , Carnitina/metabolismo , Imagen de Difusión por Resonancia Magnética , Modelos Animales de Enfermedad , Detección Precoz del Cáncer , Perfilación de la Expresión Génica , Humanos , Neoplasias Hepáticas/genética , Ratones , Ratones Transgénicos , Imagen Molecular/métodos , Carga Tumoral
5.
Proc Natl Acad Sci U S A ; 112(46): E6349-58, 2015 Nov 17.
Artículo en Inglés | MEDLINE | ID: mdl-26578795

RESUMEN

Whereas most mutations in p53 occur in the DNA-binding domain and lead to its functional inactivation, their relevance in the amino-terminal transactivation domain is unclear. We show here that amino-terminal p53 (ATp53) mutations often result in the abrogation of full-length p53 expression, but concomitantly lead to the expression of the amino-terminally truncated p47 isoform. Using genetically modified cancer cells that only express p47, we demonstrate it to be up-regulated in response to various stimuli, and to contribute to cell death, through its ability to selectively activate a group of apoptotic target genes. Target gene selectivity is influenced by K382 acetylation, which depends on the amino terminus, and is required for recruitment of selective cofactors. Consistently, cancers capable of expressing p47 had a better overall survival. Nonetheless, retention of the apoptotic function appears insufficient for tumor suppression, because these mutations are also found in the germ line and lead to Li-Fraumeni syndrome. These data from ATp53 mutations collectively demonstrate that p53's apoptosis proficiency is dispensable for tumor suppression, but could prognosticate better survival.


Asunto(s)
Transformación Celular Neoplásica/metabolismo , Regulación Neoplásica de la Expresión Génica , Síndrome de Li-Fraumeni/metabolismo , Mutación , Proteína p53 Supresora de Tumor/biosíntesis , Acetilación , Apoptosis/genética , Línea Celular Tumoral , Supervivencia Celular/genética , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Humanos , Síndrome de Li-Fraumeni/genética , Síndrome de Li-Fraumeni/patología , Isoformas de Proteínas/biosíntesis , Isoformas de Proteínas/genética , Estructura Terciaria de Proteína , Proteína p53 Supresora de Tumor/genética
6.
Nat Cell Biol ; 17(4): 511-23, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25774835

RESUMEN

The functional significance of the overexpression of unmutated TAp73, a homologue of the tumour suppressor p53, in multiple human cancers is unclear, but raises the possibility of unidentified roles in promoting tumorigenesis. We show here that TAp73 is stabilized by hypoxia, a condition highly prevalent in tumours, through HIF-1α-mediated repression of the ubiquitin ligase Siah1, which targets TAp73 for degradation. Consequently, TAp73-deficient tumours are less vascular and reduced in size, and conversely, TAp73 overexpression leads to increased vasculature. Moreover, we show that TAp73 is a critical regulator of the angiogenic transcriptome and is sufficient to directly activate the expression of several angiogenic genes.  Finally, expression of TAp73 positively correlates with these angiogenic genes in several human tumours, and the angiogenic gene signature is sufficient to segregate the TAp73(Hi)- from TAp73(Low)-expressing tumours. These data demonstrate a pro-angiogenic role for TAp73 in supporting tumorigenesis, providing a rationale for its overexpression in cancers.


Asunto(s)
Proteínas de Unión al ADN/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Neoplasias/irrigación sanguínea , Neovascularización Patológica/genética , Proteínas Nucleares/antagonistas & inhibidores , Proteínas Nucleares/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Ubiquitina-Proteína Ligasas/antagonistas & inhibidores , Animales , Hipoxia de la Célula , Línea Celular Tumoral , Transformación Celular Neoplásica/genética , Proteínas de Unión al ADN/biosíntesis , Proteínas de Unión al ADN/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Células HCT116 , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/biosíntesis , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones SCID , Proteínas Nucleares/biosíntesis , Proteínas Nucleares/genética , Unión Proteica , Proteína Tumoral p73 , Proteínas Supresoras de Tumor/biosíntesis , Proteínas Supresoras de Tumor/genética , Ubiquitina-Proteína Ligasas/genética , Ubiquitinación , Factor A de Crecimiento Endotelial Vascular/biosíntesis
7.
Cancer Cell ; 22(6): 751-64, 2012 Dec 11.
Artículo en Inglés | MEDLINE | ID: mdl-23238012

RESUMEN

The specific roles of mutant p53's dominant-negative (DN) or gain-of-function (GOF) properties in regulating acute response and long-term tumorigenesis is unclear. Using "knockin" mouse strains expressing varying R246S mutant levels, we show that the DN effect on transactivation is universally observed after acute p53 activation, whereas the effect on cellular outcome is cell-type specific. Reducing mutant p53 levels abrogated the DN effect. Mutant p53's DN effect protected against radiation-induced death but did not accentuate tumorigenesis. Furthermore, the R246S mutant did not promote tumorigenesis compared to p53(-/-) mice in various models, even when MDM2 is absent, unlike the R172H mutant. Together, these data demonstrate that mutant p53's DN property only affects acute responses, whereas GOF is not universal, being mutation-type specific.


Asunto(s)
Mutación , Activación Transcripcional , Proteína p53 Supresora de Tumor/genética , Animales , Muerte Celular/genética , Supervivencia Celular/genética , Transformación Celular Neoplásica , Células Cultivadas , Senescencia Celular/genética , Técnicas de Sustitución del Gen/métodos , Ratones , Proteínas Proto-Oncogénicas c-mdm2/genética
8.
PLoS One ; 6(1): e15320, 2011 Jan 10.
Artículo en Inglés | MEDLINE | ID: mdl-21249215

RESUMEN

Multiple single nucleotide polymorphisms (SNPs) have been identified in the tumor suppressor gene p53, though the relevance of many of them is unclear. Some of them are also differentially distributed in various ethnic populations, suggesting selective functionality. We have therefore sequenced all exons and flanking regions of p53 from the Singaporean Chinese population and report here the characterization of some novel and uncharacterized SNPs - four in intron 1 (nucleotide positions 8759/10361/10506/11130), three in intron 3 (11968/11969/11974) and two in the 3'UTR (19168/19514). Allelic frequencies were determined for all these and some known SNPs, and were compared in a limited scale to leukemia and lung cancer patient samples. Intron 2 (11827) and 7 (14181/14201) SNPs were found to have a high minor allele frequency of between 26-47%, in contrast to the lower frequencies found in the US population, but similar in trend to the codon 72 polymorphism (SNP12139) that shows a distribution pattern correlative with latitude. Several of the SNPs were linked, such as those in introns 1, 3 and 7. Most interestingly, we noticed the co-segregation of the intron 2 and the codon 72 SNPs, the latter which has been shown to be expressed in an allele-specific manner, suggesting possible regulatory cross-talk. Association analysis indicated that the T/G alleles in both the co-segregating intron 7 SNPs and a 4tagSNP haplotype was strongly associated increased susceptibility to lung cancer in non-smoker females [OR: 1.97 (1.32, 3.394)]. These data together demonstrate high SNP diversity in p53 gene between different populations, highlighting ethnicity-based differences, and their association with cancer risk.


Asunto(s)
Pueblo Asiatico/genética , Genes p53/genética , Polimorfismo de Nucleótido Simple , Regiones no Traducidas 3'/genética , Codón/genética , Etnicidad/genética , Femenino , Frecuencia de los Genes , Humanos , Intrones/genética , Leucemia/genética , Neoplasias Pulmonares/genética , Masculino , Riesgo
9.
Eur J Cancer ; 44(5): 760-6, 2008 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-18313915

RESUMEN

Although mutations in p53 are rare in leukaemia, MDM2, the negative regulator of p53, is often overexpressed. Recently, a single nucleotide polymorphism (SNP) in the MDM2 promoter--within the oestrogen-receptor-binding region--resulting in either a G or T allele was shown to affect its transcription, with elevated MDM2 being produced when it is a G allele. Expectedly, SNP309G females were found to be at a higher risk of accelerated onset of cancers. We have therefore analysed, in a pilot study, whether the status of MDM2 SNP309 and p53 codon-72 polymorphism, which was also shown to affect cancer predisposition, would affect cancer risk, onset age, overall survival and response to therapy in Chinese leukaemia patients. p53 SNP was not associated with any of the parameters. However, in contrast to expectations, the MDM2 SNP309G allele was associated with reduced risk of leukaemia. No other association was found between SNP309 and other parameters in both males and females. Thus, the data highlights ethnic differences in the effects of this SNP on cancer risk.


Asunto(s)
Genes p53/genética , Leucemia/genética , Mutación/genética , Polimorfismo de Nucleótido Simple/genética , Proteínas Proto-Oncogénicas c-mdm2/genética , Adulto , Edad de Inicio , Antineoplásicos/uso terapéutico , China/epidemiología , Femenino , Genotipo , Humanos , Leucemia/tratamiento farmacológico , Leucemia/mortalidad , Masculino , Persona de Mediana Edad , Proyectos Piloto , Factores de Riesgo , Análisis de Supervivencia
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