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1.
Proc Natl Acad Sci U S A ; 119(17): e2119644119, 2022 04 26.
Artículo en Inglés | MEDLINE | ID: mdl-35439056

RESUMEN

Missense mutations in the p53 tumor suppressor abound in human cancer. Common ("hotspot") mutations endow mutant p53 (mutp53) proteins with oncogenic gain of function (GOF), including enhanced cell migration and invasiveness, favoring cancer progression. GOF is usually attributed to transcriptional effects of mutp53. To elucidate transcription-independent effects of mutp53, we characterized the protein interactome of the p53R273H mutant in cells derived from pancreatic ductal adenocarcinoma (PDAC), where p53R273H is the most frequent p53 mutant. We now report that p53R273H, but not the p53R175H hotspot mutant, interacts with SQSTM1/p62 and promotes cancer cell migration and invasion in a p62-dependent manner. Mechanistically, the p53R273H-p62 axis drives the proteasomal degradation of several cell junction­associated proteins, including the gap junction protein Connexin 43, facilitating scattered cell migration. Concordantly, down-regulation of Connexin 43 augments PDAC cell migration, while its forced overexpression blunts the promigratory effect of the p53R273H-p62 axis. These findings define a mechanism of mutp53 GOF.


Asunto(s)
Movimiento Celular , Neoplasias Pancreáticas , Proteína p53 Supresora de Tumor , Adhesión Celular/genética , Línea Celular Tumoral , Movimiento Celular/genética , Genes p53 , Humanos , Mutación , Neoplasias Pancreáticas/genética , Proteína Sequestosoma-1/genética , Proteína Sequestosoma-1/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo
2.
Biogerontology ; 17(2): 383-93, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-26520643

RESUMEN

Naringenin, the predominant bioflavonoid found in grapefruit and tomato has diverse bioactive properties that encompass anti-carcinogenic, anti-inflammatory, anti-atherogenic, anti-estrogenic, anti-hyperlipidemic and anti-hyperglycemic characteristics. Naringenin has not been explored for its pro-longevity traits in fruit flies. Therefore, the current study explores its influence on longevity, fecundity, feeding rate, larval development, resistance to starvation stress and body weight in male and female wild-type Drosophila melanogaster Canton-S flies. Flies were fed with normal and high fat diets respectively. The results implied hormetic effects of naringenin on longevity and development in flies. In flies fed with standard and high fat diets, lower concentrations of naringenin (200 and 400 µM) augmented mean lifespan while higher concentrations (600 and 800 µM) were consistently lethal. However, enhanced longevity seen at 400 µM of naringenin was at the expense of reduced fecundity and food intake in flies. Larvae reared on standard diet having 200 µM of naringenin exhibited elevated pupation and emergence as flies. Eclosion time was hastened in larvae reared on standard diet having 200 µM of naringenin. Female flies fed with a standard diet having 200 and 400 µM of naringenin were more resistant to starvation stress. Reduction in body weight was observed in male and female flies fed with a high fat diet supplemented with 200 and 400 µM of naringenin respectively. Collectively, the results elucidated a context- and dose-dependent hormetic efficacy of naringenin that varied with gender, diet and stage of lifecycle in flies.


Asunto(s)
Drosophila melanogaster/efectos de los fármacos , Flavanonas/farmacología , Animales , Relación Dosis-Respuesta a Droga , Drosophila melanogaster/crecimiento & desarrollo , Drosophila melanogaster/fisiología , Conducta Alimentaria/efectos de los fármacos , Femenino , Fertilidad/efectos de los fármacos , Larva/efectos de los fármacos , Longevidad/efectos de los fármacos , Masculino
3.
Nat Cell Biol ; 26(8): 1336-1345, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-39103548

RESUMEN

The accumulation of senescent cells promotes ageing and age-related diseases, but molecular mechanisms that senescent cells use to evade immune clearance and accumulate in tissues remain to be elucidated. Here we report that p16-positive senescent cells upregulate the immune checkpoint protein programmed death-ligand 1 (PD-L1) to accumulate in ageing and chronic inflammation. We show that p16-mediated inhibition of cell cycle kinases CDK4/6 induces PD-L1 stability in senescent cells via downregulation of its ubiquitin-dependent degradation. p16-expressing senescent alveolar macrophages elevate PD-L1 to promote an immunosuppressive environment that can contribute to an increased burden of senescent cells. Treatment with activating anti-PD-L1 antibodies engaging Fcγ receptors on effector cells leads to the elimination of PD-L1 and p16-positive cells. Our study uncovers a molecular mechanism of p16-dependent regulation of PD-L1 protein stability in senescent cells and reveals the potential of targeting PD-L1 to improve immunosurveillance of senescent cells and ameliorate senescence-associated inflammation.


Asunto(s)
Antígeno B7-H1 , Senescencia Celular , Inhibidor p16 de la Quinasa Dependiente de Ciclina , Estabilidad Proteica , Senescencia Celular/inmunología , Antígeno B7-H1/metabolismo , Antígeno B7-H1/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Animales , Humanos , Quinasa 4 Dependiente de la Ciclina/metabolismo , Quinasa 4 Dependiente de la Ciclina/genética , Vigilancia Inmunológica , Ratones Endogámicos C57BL , Quinasa 6 Dependiente de la Ciclina/metabolismo , Quinasa 6 Dependiente de la Ciclina/genética , Ratones , Proteolisis , Receptores de IgG/metabolismo , Inflamación/inmunología , Inflamación/metabolismo , Inflamación/patología , Inflamación/genética
4.
Cell Rep Med ; 5(9): 101703, 2024 Sep 17.
Artículo en Inglés | MEDLINE | ID: mdl-39216477

RESUMEN

Activating EGFR (epidermal growth factor receptor) mutations can be inhibited by specific tyrosine kinase inhibitors (TKIs), which have changed the landscape of lung cancer therapy. However, due to secondary mutations and bypass receptors, such as AXL (AXL receptor tyrosine kinase), drug resistance eventually emerges in most patients treated with the first-, second-, or third-generation TKIs (e.g., osimertinib). To inhibit AXL and resistance to osimertinib, we compare two anti-AXL drugs, an antibody (mAb654) and a TKI (bemcentinib). While no pair of osimertinib and an anti-AXL drug is able to prevent relapses, triplets combining osimertinib, cetuximab (an anti-EGFR antibody), and either anti-AXL drug are initially effective. However, longer monitoring uncovers superiority of the mAb654-containing triplet, possibly due to induction of receptor endocytosis, activation of immune mechanisms, or disabling intrinsic mutators. Hence, we constructed a bispecific antibody that engages both AXL and EGFR. When combined with osimertinib, the bispecific antibody consistently inhibits tumor relapses, which warrants clinical trials.


Asunto(s)
Acrilamidas , Compuestos de Anilina , Anticuerpos Biespecíficos , Tirosina Quinasa del Receptor Axl , Resistencia a Antineoplásicos , Receptores ErbB , Proteínas Proto-Oncogénicas , Proteínas Tirosina Quinasas Receptoras , Humanos , Acrilamidas/farmacología , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Proteínas Tirosina Quinasas Receptoras/genética , Proteínas Tirosina Quinasas Receptoras/inmunología , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Compuestos de Anilina/farmacología , Compuestos de Anilina/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Anticuerpos Biespecíficos/farmacología , Animales , Línea Celular Tumoral , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/genética , Ratones , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Cetuximab/farmacología , Cetuximab/uso terapéutico , Ensayos Antitumor por Modelo de Xenoinjerto , Femenino , Indoles , Pirimidinas
5.
Cancer Discov ; 12(11): 2666-2683, 2022 11 02.
Artículo en Inglés | MEDLINE | ID: mdl-35895872

RESUMEN

Anticancer therapies have been limited by the emergence of mutations and other adaptations. In bacteria, antibiotics activate the SOS response, which mobilizes error-prone factors that allow for continuous replication at the cost of mutagenesis. We investigated whether the treatment of lung cancer with EGFR inhibitors (EGFRi) similarly engages hypermutators. In cycling drug-tolerant persister (DTP) cells and in EGFRi-treated patients presenting residual disease, we observed upregulation of GAS6, whereas ablation of GAS6's receptor, AXL, eradicated resistance. Reciprocally, AXL overexpression enhanced DTP survival and accelerated the emergence of T790M, an EGFR mutation typical to resistant cells. Mechanistically, AXL induces low-fidelity DNA polymerases and activates their organizer, RAD18, by promoting neddylation. Metabolomics uncovered another hypermutator, AXL-driven activation of MYC, and increased purine synthesis that is unbalanced by pyrimidines. Aligning anti-AXL combination treatments with the transition from DTPs to resistant cells cured patient-derived xenografts. Hence, similar to bacteria, tumors tolerate therapy by engaging pharmacologically targetable endogenous mutators. SIGNIFICANCE: EGFR-mutant lung cancers treated with kinase inhibitors often evolve resistance due to secondary mutations. We report that in similarity to the bacterial SOS response stimulated by antibiotics, endogenous mutators are activated in drug-treated cells, and this heralds tolerance. Blocking the process prevented resistance in xenograft models, which offers new treatment strategies. This article is highlighted in the In This Issue feature, p. 2483.


Asunto(s)
Resistencia a Antineoplásicos , Neoplasias Pulmonares , Proteínas Proto-Oncogénicas , Proteínas Tirosina Quinasas Receptoras , Humanos , Línea Celular Tumoral , Replicación del ADN , Proteínas de Unión al ADN/genética , Resistencia a Antineoplásicos/genética , Receptores ErbB/genética , Neoplasias Pulmonares/genética , Mutación , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas/genética , Proteínas Tirosina Quinasas Receptoras/genética , Ubiquitina-Proteína Ligasas/genética , Animales , Tirosina Quinasa del Receptor Axl
6.
Fly (Austin) ; 9(1): 16-21, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26252611

RESUMEN

Drosophila melanogaster is an ideal model organism for developmental studies. This study tests the potential of semolina-jaggery (SJ) diet as a new formulation for bulk rearing of flies. Semolina and jaggery are organic products obtained from wheat endosperm and cane sugar, respectively. Semolina is a rich source of carbohydrates and protein. Jaggery has a high content of dietary sugars. Moreover, preparation of semolina jaggery diet is cost-effective and easy. Thus, the current study aimed to compare survival and developmental parameters of flies fed the SJ diet to flies fed the standard cornmeal-sugar-yeast (CSY) diet. SJ diet enhanced survival of flies without affecting fecundity; male flies showed increased resistance to starvation. A higher number of flies emerged at F2 and F3 generation when fed the SJ diet than when fed the control CSY diet. SJ diet did not increase fly body weight and lipid percentage. Therefore, SJ diet can be used for bulk rearing of healthy flies at par with the standard cornmeal-sugar-yeast diet.


Asunto(s)
Alimentación Animal/estadística & datos numéricos , Dieta , Drosophila melanogaster/crecimiento & desarrollo , Animales , Peso Corporal , Femenino , Fertilidad , Privación de Alimentos , Larva/crecimiento & desarrollo , Lípidos/análisis , Longevidad , Masculino , Extractos Vegetales , Triticum
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