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1.
Mol Cell ; 81(18): 3848-3865.e19, 2021 09 16.
Artículo en Inglés | MEDLINE | ID: mdl-34547241

RESUMEN

Metabolic rewiring and redox balance play pivotal roles in cancer. Cellular senescence is a barrier for tumorigenesis circumvented in cancer cells by poorly understood mechanisms. We report a multi-enzymatic complex that reprograms NAD metabolism by transferring reducing equivalents from NADH to NADP+. This hydride transfer complex (HTC) is assembled by malate dehydrogenase 1, malic enzyme 1, and cytosolic pyruvate carboxylase. HTC is found in phase-separated bodies in the cytosol of cancer or hypoxic cells and can be assembled in vitro with recombinant proteins. HTC is repressed in senescent cells but induced by p53 inactivation. HTC enzymes are highly expressed in mouse and human prostate cancer models, and their inactivation triggers senescence. Exogenous expression of HTC is sufficient to bypass senescence, rescue cells from complex I inhibitors, and cooperate with oncogenic RAS to transform primary cells. Altogether, we provide evidence for a new multi-enzymatic complex that reprograms metabolism and overcomes cellular senescence.


Asunto(s)
Senescencia Celular/fisiología , NAD/metabolismo , Envejecimiento/metabolismo , Envejecimiento/fisiología , Animales , Línea Celular Tumoral , Senescencia Celular/genética , Citosol , Glucosa/metabolismo , Humanos , Hidrógeno/química , Hidrógeno/metabolismo , Malato Deshidrogenasa/metabolismo , Masculino , Ratones , Ratones Endogámicos NOD , Ratones Transgénicos , NAD/fisiología , Oxidación-Reducción , Piruvato Carboxilasa/metabolismo , Ácido Pirúvico/metabolismo
2.
Cancer Res ; 79(13): 3306-3319, 2019 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-31101761

RESUMEN

Expression of the suppressor of cytokine signaling-1 (SOCS1) is inactivated in hematopoietic and solid cancers by promoter methylation, miRNA-mediated silencing, and mutations. Paradoxically, SOCS1 is also overexpressed in many human cancers. We report here that the ability of SOCS1 to interact with p53 and regulate cellular senescence depends on a structural motif that includes tyrosine (Y)80 in the SH2 domain of SOCS1. Mutations in this motif are found at low frequency in some human cancers, and substitution of Y80 by a phosphomimetic residue inhibits p53-SOCS1 interaction and its functional consequences, including stimulation of p53 transcriptional activity, growth arrest, and cellular senescence. Mass spectrometry confirmed SOCS1 Y80 phosphorylation in cells, and a new mAb was generated to detect its presence in tissues by IHC. A tyrosine kinase library screen identified the SRC family as Y80-SOCS1 kinases. SRC family kinase inhibitors potentiated the SOCS1-p53 pathway and reinforced SOCS1-induced senescence. Samples from human lymphomas that often overexpress SOCS1 also displayed SRC family kinase activation, constitutive phosphorylation of SOCS1 on Y80, and SOCS1 cytoplasmic localization. Collectively, these results reveal a mechanism that inactivates the SOCS1-p53 senescence pathway and suggest that inhibition of SRC family kinases as personalized treatment in patients with lymphomas may be successful. SIGNIFICANCE: These findings show that SOCS1 phosphorylation by the SRC family inhibits its tumor-suppressive activity, indicating that patients with increased SOCS1 phosphorylation may benefit from SRC family kinase inhibitors.


Asunto(s)
Senescencia Celular , Linfoma/patología , Dominios y Motivos de Interacción de Proteínas , Proteína 1 Supresora de la Señalización de Citocinas/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Familia-src Quinasas/metabolismo , Humanos , Linfoma/genética , Linfoma/metabolismo , Fosforilación , Transducción de Señal , Proteína 1 Supresora de la Señalización de Citocinas/genética , Células Tumorales Cultivadas , Proteína p53 Supresora de Tumor/genética , Tirosina/química , Tirosina/genética , Tirosina/metabolismo , Dominios Homologos src , Familia-src Quinasas/genética
3.
Bioorg Med Chem ; 26(20): 5547-5554, 2018 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-30309670

RESUMEN

Lamin A contributes to the structure of nuclei in all mammalian cells and plays an important role in cell division and migration. Mature lamin A is derived from a farnesylated precursor protein, known as prelamin A, which undergoes post-translational cleavage catalyzed by the zinc metalloprotease STE24 (ZPMSTE24). Accumulation of farnesylated prelamin A in the nuclear envelope compromises cell division, impairs mitosis and induces an increased expression of inflammatory gene products. ZMPSTE24 has been proposed as a potential therapeutic target in oncology. A library of peptidomimetic compounds were synthesized and screened for their ability to induce accumulation of prelamin A in cancer cells and block cell migration in pancreatic ductal adenocarcinoma cells. The results of this study suggest that inhibitors of lamin A maturation may interfere with cell migration, the biological process required for cancer metastasis.


Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Movimiento Celular/efectos de los fármacos , Lamina Tipo A/metabolismo , Peptidomiméticos/química , Peptidomiméticos/farmacología , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Antineoplásicos/síntesis química , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Humanos , Proteínas de la Membrana/metabolismo , Metaloendopeptidasas/metabolismo , Invasividad Neoplásica/patología , Invasividad Neoplásica/prevención & control , Peptidomiméticos/síntesis química , Ácidos Fosfínicos/síntesis química , Ácidos Fosfínicos/química , Ácidos Fosfínicos/farmacología
4.
Nat Cell Biol ; 20(7): 789-799, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-29941930

RESUMEN

Cellular senescence is a tumour suppressor programme characterized by a stable cell cycle arrest. Here we report that cellular senescence triggered by a variety of stimuli leads to diminished ribosome biogenesis and the accumulation of both rRNA precursors and ribosomal proteins. These defects were associated with reduced expression of several ribosome biogenesis factors, the knockdown of which was also sufficient to induce senescence. Genetic analysis revealed that Rb but not p53 was required for the senescence response to altered ribosome biogenesis. Mechanistically, the ribosomal protein S14 (RPS14 or uS11) accumulates in the soluble non-ribosomal fraction of senescent cells, where it binds and inhibits CDK4 (cyclin-dependent kinase 4). Overexpression of RPS14 is sufficient to inhibit Rb phosphorylation, inducing cell cycle arrest and senescence. Here we describe a mechanism for maintaining the senescent cell cycle arrest that may be relevant for cancer therapy, as well as biomarkers to identify senescent cells.


Asunto(s)
Puntos de Control del Ciclo Celular , Senescencia Celular , Neoplasias/metabolismo , Proteína de Retinoblastoma/metabolismo , Ribosomas/metabolismo , Factores de Coagulación Sanguínea/genética , Factores de Coagulación Sanguínea/metabolismo , Quinasa 4 Dependiente de la Ciclina/genética , Quinasa 4 Dependiente de la Ciclina/metabolismo , Células HEK293 , Humanos , Neoplasias/genética , Neoplasias/patología , Células PC-3 , Fosforilación , Unión Proteica , Precursores del ARN/biosíntesis , Precursores del ARN/genética , ARN Ribosómico/biosíntesis , ARN Ribosómico/genética , Proteínas de Unión al ARN , Proteína de Retinoblastoma/genética , Proteínas Ribosómicas/genética , Proteínas Ribosómicas/metabolismo , Ribosomas/genética , Transducción de Señal , Factores de Tiempo
5.
Cancer Res ; 76(11): 3252-64, 2016 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-27206849

RESUMEN

Promyelocytic leukemia (PML) plays a tumor suppressive role by inducing cellular senescence in response to oncogenic stress. However, tumor cell lines fail to engage in complete senescence upon PML activation. In this study, we investigated the mechanisms underlying resistance to PML-induced senescence. Here, we report that activation of the cyclin-dependent kinases CDK4 and CDK6 are essential and sufficient to impair senescence induced by PML expression. Disrupting CDK function by RNA interference or pharmacological inhibition restored senescence in tumor cells and diminished their tumorigenic potential in mouse xenograft models. Complete senescence correlated with an increase in autophagy, repression of E2F target genes, and an gene expression signature of blocked DNA methylation. Accordingly, treatment of tumor cells with inhibitors of DNA methylation reversed resistance to PML-induced senescence. Further, CDK inhibition with palbociclib promoted autophagy-dependent degradation of the DNA methyltransferase DNMT1. Lastly, we found that CDK4 interacted with and phosphorylated DNMT1 in vitro, suggesting that CDK activity is required for its stabilization. Taken together, our findings highlight a potentially valuable feature of CDK4/6 inhibitors as epigenetic modulators to facilitate activation of senescence programs in tumor cells. Cancer Res; 76(11); 3252-64. ©2016 AACR.


Asunto(s)
Senescencia Celular/genética , Quinasa 4 Dependiente de la Ciclina/genética , Quinasa 6 Dependiente de la Ciclina/genética , Epigénesis Genética/genética , Regulación Neoplásica de la Expresión Génica , Proteína de la Leucemia Promielocítica/metabolismo , Neoplasias de la Próstata/genética , Animales , Apoptosis , Western Blotting , Ciclo Celular , Proliferación Celular , Quinasa 4 Dependiente de la Ciclina/metabolismo , Quinasa 6 Dependiente de la Ciclina/metabolismo , Metilación de ADN , Perfilación de la Expresión Génica , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Fosforilación , Proteína de la Leucemia Promielocítica/genética , Neoplasias de la Próstata/enzimología , Neoplasias de la Próstata/patología , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
6.
Aging (Albany NY) ; 8(2): 366-81, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26922519

RESUMEN

Mutants of lamin A cause diseases including the Hutchinson-Gilford progeria syndrome (HGPS) characterized by premature aging. Lamin A undergoes a series of processing reactions, including farnesylation and proteolytic cleavage of the farnesylated C-terminal domain. The role of cleavage is unknown but mutations that affect this reaction lead to progeria. Here we show that interphase serine 22 phosphorylation of endogenous mutant lamin A (progerin) is defective in cells from HGPS patients. This defect can be mimicked by expressing progerin in human cells and prevented by inhibition of farnesylation. Furthermore, serine 22 phosphorylation of non-farnesylated progerin was enhanced by a mutation that disrupts lamin A head to tail interactions. The phosphorylation of lamin A or non-farnesylated progerin was associated to the formation of spherical intranuclear lamin A droplets that accumulate protein kinases of the CDK family capable of phosphorylating lamin A at serine 22. CDK inhibitors compromised the turnover of progerin, accelerated senescence of HGPS cells and reversed the effects of FTI on progerin levels. We discuss a model of progeria where faulty serine 22 phosphorylation compromises phase separation of lamin A polymers, leading to accumulation of functionally impaired lamin A structures.


Asunto(s)
Interfase , Lamina Tipo A/genética , Lamina Tipo A/metabolismo , Progeria/genética , Progeria/metabolismo , Humanos , Immunoblotting , Inmunoprecipitación , Microscopía Fluorescente , Mutagénesis Sitio-Dirigida , Mutación , Fosforilación , Prenilación de Proteína , Serina/metabolismo
7.
Mol Biol Cell ; 25(5): 554-65, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24403608

RESUMEN

The expression of the forkhead transcription factor checkpoint suppressor 1 (CHES1), also known as FOXN3, is reduced in many types of cancers. We show here that CHES1 decreases protein synthesis and cell proliferation in tumor cell lines but not in normal fibroblasts. Conversely, short hairpin RNA-mediated depletion of CHES1 increases tumor cell proliferation. Growth suppression depends on the CHES1 forkhead DNA-binding domain and correlates with the nuclear localization of CHES1. CHES1 represses the expression of multiple genes, including the kinases PIM2 and DYRK3, which regulate protein biosynthesis, and a number of genes in cilium biogenesis. CHES1 binds directly to the promoter of PIM2, and in cells expressing CHES1 the levels of PIM2 are reduced, as well as the phosphorylation of the PIM2 target 4EBP1. Overexpression of PIM2 or eIF4E partially reverses the antiproliferative effect of CHES1, indicating that PIM2 and protein biosynthesis are important targets of the antiproliferative effect of CHES1. In several human hematopoietic cancers, CHES1 and PIM2 expressions are inversely correlated, suggesting that repression of PIM2 by CHES1 is clinically relevant.


Asunto(s)
Proteínas de Ciclo Celular/fisiología , Proliferación Celular , Biosíntesis de Proteínas/genética , Proteínas Serina-Treonina Quinasas/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Represoras/fisiología , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Fibroblastos/metabolismo , Factores de Transcripción Forkhead , Regulación Neoplásica de la Expresión Génica , Humanos , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Represoras/genética , Proteínas Represoras/metabolismo
8.
Aging Cell ; 12(3): 489-98, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-23521863

RESUMEN

We show that the antidiabetic drug metformin inhibits the expression of genes coding for multiple inflammatory cytokines seen during cellular senescence. Conditioned medium (CM) from senescent cells stimulates the growth of prostate cancer cells but treatment of senescent cells with metformin inhibited this effect. Bioinformatic analysis of genes downregulated by metformin suggests that the drug blocks the activity of the transcription factor NF-κB. In agreement, metformin prevented the translocation of NF-κB to the nucleus and inhibited the phosphorylation of IκB and IKKα/ß, events required for activation of the NF-κB pathway. These effects were not dependent on AMPK activation or on the context of cellular senescence, as metformin inhibited the NF-κB pathway stimulated by lipopolysaccharide (LPS) in ampk null fibroblasts and in macrophages. Taken together, our results provide a novel mechanism for the antiaging and antineoplastic effects of metformin reported in animal models and in diabetic patients taking this drug.


Asunto(s)
Senescencia Celular/efectos de los fármacos , Quinasa I-kappa B/metabolismo , Metformina/farmacología , FN-kappa B/metabolismo , Factor de Transcripción ReIA/metabolismo , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Medios de Cultivo Condicionados , Citocinas/metabolismo , Activación Enzimática/efectos de los fármacos , Fibroblastos/efectos de los fármacos , Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica , Humanos , Hipoglucemiantes/farmacología , Inflamación/genética , Lipopolisacáridos/farmacología , Macrófagos/efectos de los fármacos , Masculino , Ratones , Fosforilación/efectos de los fármacos , Neoplasias de la Próstata , Interferencia de ARN , ARN Interferente Pequeño , Transducción de Señal/efectos de los fármacos , Factor de Transcripción ReIA/genética , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
9.
J Biol Chem ; 282(48): 34938-44, 2007 Nov 30.
Artículo en Inglés | MEDLINE | ID: mdl-17913706

RESUMEN

Senescence is a general antiproliferative program that avoids the expansion of cells bearing oncogenic mutations. We found that constitutively active STAT5A (ca-STAT5A) can induce a p53- and Rb-dependent cellular senescence response. However, ca-STAT5A did not induce p21 and p16(INK4a), which are responsible for inhibiting cyclin-dependent protein kinases and engaging the Rb pathway during the senescence response to oncogenic ras. Intriguingly, ca-STAT5A led to a down-regulation of Myc and Myc targets, including CDK4, a negative regulator of Rb. The down-regulation of Myc was in part proteasome-dependent and correlated with its localization to promyelocytic leukemia bodies, which were found to be highly abundant during STAT5-induced senescence. Introduction of CDK4 or Myc bypassed STAT5A-induced senescence in cells in which p53 was also inactivated. These results uncover a novel mechanism to engage the Rb pathway in oncogene-induced senescence and indicate the existence of oncogene-specific pathways that regulate senescence.


Asunto(s)
Regulación hacia Abajo , Proteínas Proto-Oncogénicas c-myc/fisiología , Proteína de Retinoblastoma/metabolismo , Factor de Transcripción STAT5/metabolismo , Línea Celular , Línea Celular Tumoral , Núcleo Celular/metabolismo , Proliferación Celular , Senescencia Celular , Quinasa 4 Dependiente de la Ciclina/metabolismo , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Fibroblastos/metabolismo , Humanos , Modelos Biológicos , Complejo de la Endopetidasa Proteasomal/metabolismo , Proteínas Proto-Oncogénicas c-myc/biosíntesis , Transducción de Señal , Proteína p53 Supresora de Tumor/metabolismo , Proteínas Supresoras de Tumor
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