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1.
Cell Death Discov ; 10(1): 292, 2024 Jun 19.
Artículo en Inglés | MEDLINE | ID: mdl-38897995

RESUMEN

Cancer metabolic reprogramming has been recognized as one of the cancer hallmarks that promote cell proliferation, survival, as well as therapeutic resistance. Up-to-date regulation of metabolism in T-cell lymphoma is poorly understood. In particular, for human angioimmunoblastic T-cell lymphoma (AITL) the metabolic profile is not known. Metabolic intervention could help identify new treatment options for this cancer with very poor outcomes and no effective medication. Transcriptomic analysis of AITL tumor cells, identified that these cells use preferentially mitochondrial metabolism. By using our preclinical AITL mouse model, mimicking closely human AITL features, we confirmed that T follicular helper (Tfh) tumor cells exhibit a strong enrichment of mitochondrial metabolic signatures. Consistent with these results, disruption of mitochondrial metabolism using metformin or a mitochondrial complex I inhibitor such as IACS improved the survival of AITL lymphoma-bearing mice. Additionally, we confirmed a selective elimination of the malignant human AITL T cells in patient biopsies upon mitochondrial respiration inhibition. Moreover, we confirmed that diabetic patients suffering from T-cell lymphoma, treated with metformin survived longer as compared to patients receiving alternative treatments. Taking together, our findings suggest that targeting the mitochondrial metabolic pathway could be a clinically efficient approach to inhibit aggressive cancers such as peripheral T-cell lymphoma.

2.
Cell Death Dis ; 15(5): 334, 2024 May 14.
Artículo en Inglés | MEDLINE | ID: mdl-38744890

RESUMEN

The prevalence of diabetes steadily increases worldwide mirroring the prevalence of obesity. Endoplasmic reticulum (ER) stress is activated in diabetes and contributes to ß-cell dysfunction and apoptosis through the activation of a terminal unfolded protein response (UPR). Our results uncover a new role for Bax Inhibitor-One (BI-1), a negative regulator of inositol-requiring enzyme 1 (IRE1α) in preserving ß-cell health against terminal UPR-induced apoptosis and pyroptosis in the context of supraphysiological loads of insulin production. BI-1-deficient mice experience a decline in endocrine pancreatic function in physiological and pathophysiological conditions, namely obesity induced by high-fat diet (HFD). We observed early-onset diabetes characterized by hyperglycemia, reduced serum insulin levels, ß-cell loss, increased pancreatic lipases and pro-inflammatory cytokines, and the progression of metabolic dysfunction. Pancreatic section analysis revealed that BI-1 deletion overburdens unfolded proinsulin in the ER of ß-cells, confirmed by ultrastructural signs of ER stress with overwhelmed IRE1α endoribonuclease (RNase) activity in freshly isolated islets. ER stress led to ß-cell dysfunction and islet loss, due to an increase in immature proinsulin granules and defects in insulin crystallization with the presence of Rod-like granules. These results correlated with the induction of autophagy, ER phagy, and crinophagy quality control mechanisms, likely to alleviate the atypical accumulation of misfolded proinsulin in the ER. In fine, BI-1 in ß-cells limited IRE1α RNase activity from triggering programmed ß-cell death through apoptosis and pyroptosis (caspase-1, IL-1ß) via NLRP3 inflammasome activation and metabolic dysfunction. Pharmaceutical IRE1α inhibition with STF-083010 reversed ß-cell failure and normalized the metabolic phenotype. These results uncover a new protective role for BI-1 in pancreatic ß-cell physiology as a stress integrator to modulate the UPR triggered by accumulating unfolded proinsulin in the ER, as well as autophagy and programmed cell death, with consequences on ß-cell function and insulin secretion. In pancreatic ß-cells, BI-1-/- deficiency perturbs proteostasis with proinsulin misfolding, ER stress, terminal UPR with overwhelmed IRE1α/XBP1s/CHOP activation, inflammation, ß-cell programmed cell death, and diabetes.


Asunto(s)
Apoptosis , Estrés del Retículo Endoplásmico , Células Secretoras de Insulina , Proteínas de la Membrana , Proinsulina , Proteostasis , Respuesta de Proteína Desplegada , Animales , Ratones , Dieta Alta en Grasa , Endorribonucleasas/metabolismo , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patología , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Ratones Endogámicos C57BL , Ratones Noqueados , Proinsulina/metabolismo , Pliegue de Proteína
3.
Cell Stem Cell ; 30(6): 800-817.e9, 2023 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-37267915

RESUMEN

Cholesterol efflux pathways could be exploited in tumor biology to unravel cancer vulnerabilities. A mouse model of lung-tumor-bearing KRASG12D mutation with specific disruption of cholesterol efflux pathways in epithelial progenitor cells promoted tumor growth. Defective cholesterol efflux in epithelial progenitor cells governed their transcriptional landscape to support their expansion and create a pro-tolerogenic tumor microenvironment (TME). Overexpression of the apolipoprotein A-I, to raise HDL levels, protected these mice from tumor development and dire pathologic consequences. Mechanistically, HDL blunted a positive feedback loop between growth factor signaling pathways and cholesterol efflux pathways that cancer cells hijack to expand. Cholesterol removal therapy with cyclodextrin reduced tumor burden in progressing tumor by suppressing the proliferation and expansion of epithelial progenitor cells of tumor origin. Local and systemic perturbations of cholesterol efflux pathways were confirmed in human lung adenocarcinoma (LUAD). Our results position cholesterol removal therapy as a putative metabolic target in lung cancer progenitor cells.


Asunto(s)
Neoplasias Pulmonares , Proteínas Proto-Oncogénicas p21(ras) , Humanos , Ratones , Animales , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Colesterol/metabolismo , Neoplasias Pulmonares/genética , Proliferación Celular , Pulmón , Células Madre/metabolismo , Apolipoproteína A-I/metabolismo , Microambiente Tumoral
4.
Br J Dermatol ; 189(3): 312-327, 2023 08 24.
Artículo en Inglés | MEDLINE | ID: mdl-37140010

RESUMEN

BACKGROUND: Vitiligo is an autoimmune skin disorder characterized by loss of melanocytes. Protease-mediated disruption of junctions between keratinocytes and/or keratinocyte intrinsic dysfunction may directly contribute to melanocyte loss. House dust mite (HDM), an environmental allergen with potent protease activity, contributes to respiratory and gut disease but also to atopic dermatitis and rosacea. OBJECTIVES: To verify if HDM can contribute to melanocyte detachment in vitiligo and if so, by which mechanism(s). METHODS: Using primary human keratinocytes, human skin biopsies from healthy donors and patients with vitiligo, and 3D reconstructed human epidermis, we studied the effect of HDM on cutaneous immunity, tight and adherent junction expression and melanocyte detachment. RESULTS: HDM increased keratinocyte production of vitiligo-associated cytokines and chemokines and increased expression of toll-like receptor (TLR)-4. This was associated with increased in situ matrix-metalloproteinase (MMP)-9 activity, reduced cutaneous expression of adherent protein E-cadherin, increased soluble E-cadherin in culture supernatant and significantly increased number of suprabasal melanocytes in the skin. This effect was dose-dependent and driven by cysteine protease Der p1 and MMP-9. Selective MMP-9 inhibitor, Ab142180, restored E-cadherin expression and inhibited HDM-induced melanocyte detachment. Keratinocytes from patients with vitiligo were more sensitive to HDM-induced changes than healthy keratinocytes. All results were confirmed in a 3D model of healthy skin and in human skin biopsies. CONCLUSIONS: Our results highlight that environmental mite may act as an external source of pathogen-associated molecular pattern molecules in vitiligo and topical MMP-9 inhibitors may be useful therapeutic targets. Whether HDM contributes to the onset of flares in vitiligo remains to be tested in carefully controlled trials.


Asunto(s)
Vitíligo , Animales , Humanos , Vitíligo/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/farmacología , Pyroglyphidae , Melanocitos/metabolismo , Queratinocitos/metabolismo , Cadherinas/metabolismo
5.
Oncoimmunology ; 11(1): 2116844, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36046811

RESUMEN

IRE1α is one of the three ER transmembrane transducers of the Unfolded Protein Response (UPR) activated under endoplasmic reticulum (ER) stress. IRE1α activation has a dual role in cancer as it may be either pro- or anti-tumoral depending on the studied models. Here, we describe the discovery that exogenous expression of IRE1α, resulting in IRE1α auto-activation, did not affect cancer cell proliferation in vitro but resulted in a tumor-suppressive phenotype in syngeneic immunocompetent mice. We found that exogenous expression of IRE1α in murine colorectal and Lewis lung carcinoma cells impaired tumor growth when syngeneic tumor cells were subcutaneously implanted in immunocompetent mice but not in immunodeficient mice. Mechanistically, the in vivo tumor-suppressive effect of overexpressing IRE1α in tumor cells was associated with IRE1α RNAse activity driving both XBP1 mRNA splicing and regulated IRE1-dependent decay of RNA (RIDD). We showed that the tumor-suppressive phenotype upon IRE1α overexpression was characterized by the induction of apoptosis in tumor cells along with an enhanced adaptive anti-cancer immunosurveillance. Hence, our work indicates that IRE1α overexpression and/or activation in tumor cells can limit tumor growth in immunocompetent mice. This finding might point toward the need of adjusting the use of IRE1α inhibitors in cancer treatments based on the predominant outcome of the RNAse activity of IRE1α.


Asunto(s)
Endorribonucleasas , Neoplasias , Animales , Endorribonucleasas/genética , Endorribonucleasas/metabolismo , Inmunidad , Ratones , Procesos Neoplásicos , Proteínas Serina-Treonina Quinasas/genética , Transducción de Señal , Proteína 1 de Unión a la X-Box/genética , Proteína 1 de Unión a la X-Box/metabolismo
6.
Sci Adv ; 8(27): eabn6491, 2022 07 08.
Artículo en Inglés | MEDLINE | ID: mdl-35857457

RESUMEN

Depletion of circulating asparagine with l-asparaginase (ASNase) is a mainstay of leukemia treatment and is under investigation in many cancers. Expression levels of asparagine synthetase (ASNS), which catalyzes asparagine synthesis, were considered predictive of cancer cell sensitivity to ASNase treatment, a notion recently challenged. Using [U-13C5]-l-glutamine in vitro and in vivo in a mouse model of B cell lymphomas (BCLs), we demonstrated that supraphysiological or physiological concentrations of asparagine prevent de novo asparagine biosynthesis, regardless of ASNS expression levels. Overexpressing ASNS in ASNase-sensitive BCL was insufficient to confer resistance to ASNase treatment in vivo. Moreover, we showed that ASNase's glutaminase activity enables its maximal anticancer effect. Together, our results indicate that baseline ASNS expression (low or high) cannot dictate BCL dependence on de novo asparagine biosynthesis and predict BCL sensitivity to dual ASNase activity. Thus, except for ASNS-deficient cancer cells, ASNase's glutaminase activity should be considered in the clinic.


Asunto(s)
Antineoplásicos , Aspartatoamoníaco Ligasa , Linfoma de Células B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Animales , Antineoplásicos/uso terapéutico , Asparaginasa/uso terapéutico , Asparagina/metabolismo , Aspartatoamoníaco Ligasa/genética , Aspartatoamoníaco Ligasa/metabolismo , Línea Celular Tumoral , Glutaminasa/uso terapéutico , Linfoma de Células B/tratamiento farmacológico , Ratones , Microambiente Tumoral
8.
Oncogenesis ; 10(9): 64, 2021 Sep 27.
Artículo en Inglés | MEDLINE | ID: mdl-34580273

RESUMEN

Fluorizoline is a prohibitin-binding compound that triggers apoptosis in several cell lines from murine and human origin, as well as in primary cells from hematologic malignancies by inducing the integrated stress response and ER stress. Recently, it was described that PHB (Prohibitin) 1 and 2 are crucial mitophagy receptors involved in mediating the autophagic degradation of mitochondria. We measured mitophagy in HeLa cells expressing Parkin and in A549, a lung cancer cell line that can undergo mitophagy in a Parkin-independent manner, and we demonstrated that both fluorizoline and rocaglamide A, another PHB-binding molecule, inhibit CCCP- and OA-induced mitophagy. Moreover, we demonstrated that PHBs are mediating Parkin-dependent mitophagy. In conclusion, besides being a potent pro-apoptotic compound, we present fluorizoline as a promising new mitophagy modulator that could be used as anticancer agent.

9.
Nat Microbiol ; 6(3): 401-412, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33432150

RESUMEN

Inflammasomes are signalling platforms that are assembled in response to infection or sterile inflammation by cytosolic pattern recognition receptors. The consequent inflammasome-triggered caspase-1 activation is critical for the host defence against pathogens. During infection, NLRP3, which is a pattern recognition receptor that is also known as cryopyrin, triggers the assembly of the inflammasome-activating caspase-1 through the recruitment of ASC and Nek7. The activation of the NLRP3 inflammasome is tightly controlled both transcriptionally and post-translationally. Despite the importance of the NLRP3 inflammasome regulation in autoinflammatory and infectious diseases, little is known about the mechanism controlling the activation of NLRP3 and the upstream signalling that regulates the NLRP3 inflammasome assembly. We have previously shown that the Rho-GTPase-activating toxin from Escherichia coli cytotoxic necrotizing factor-1 (CNF1) activates caspase-1, but the upstream mechanism is unclear. Here, we provide evidence of the role of the NLRP3 inflammasome in sensing the activity of bacterial toxins and virulence factors that activate host Rho GTPases. We demonstrate that this activation relies on the monitoring of the toxin's activity on the Rho GTPase Rac2. We also show that the NLRP3 inflammasome is activated by a signalling cascade that involves the p21-activated kinases 1 and 2 (Pak1/2) and the Pak1-mediated phosphorylation of Thr 659 of NLRP3, which is necessary for the NLRP3-Nek7 interaction, inflammasome activation and IL-1ß cytokine maturation. Furthermore, inhibition of the Pak-NLRP3 axis decreases the bacterial clearance of CNF1-expressing UTI89 E. coli during bacteraemia in mice. Taken together, our results establish that Pak1 and Pak2 are critical regulators of the NLRP3 inflammasome and reveal the role of the Pak-NLRP3 signalling axis in vivo during bacteraemia in mice.


Asunto(s)
Bacteriemia/metabolismo , Toxinas Bacterianas/metabolismo , Infecciones por Escherichia coli/metabolismo , Proteínas de Escherichia coli/metabolismo , Escherichia coli/metabolismo , Inflamasomas/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteínas de Unión al GTP rac/metabolismo , Animales , Bacteriemia/inmunología , Bacteriemia/microbiología , Carga Bacteriana , Toxinas Bacterianas/genética , Escherichia coli/genética , Infecciones por Escherichia coli/inmunología , Infecciones por Escherichia coli/microbiología , Proteínas de Escherichia coli/genética , Inmunidad Innata , Ratones , Fosforilación , Transducción de Señal , Quinasas p21 Activadas/metabolismo , Proteínas de Unión al GTP rac/genética , Proteína RCA2 de Unión a GTP
10.
FEBS J ; 288(11): 3547-3569, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33340237

RESUMEN

Myocardial ischemia/reperfusion (I/R) injury is a frequent perioperative threat, with numerous strategies developed to limit and/or prevent it. One interesting axis of research is the anesthetic preconditioning (APc) agent's hypothesis (such as sevoflurane, SEV). However, APc's mode of action is still poorly understood and volatile anesthetics used as preconditioning agents are often not well suited in clinical practice. Here, in vitro using H9C2 cells lines (in myeloblast state or differentiated toward cardiomyocytes) and in vivo in mice, we identified that SEV-induced APc is mediated by a mild induction of reactive oxygen species (ROS) that activates Akt and induces the expression of the anti-apoptotic protein B-cell lymphoma-extra large (Bcl-xL), therefore protecting cardiomyocytes from I/R-induced death. Furthermore, we extended these results to human cardiomyocytes (derived from induced pluripotent stem - IPS - cells). Importantly, we demonstrated that this protective signaling pathway induced by SEV could be stimulated using the antidiabetic agent metformin (MET), suggesting the preconditioning properties of MET. Altogether, our study identified a signaling pathway allowing APc of cardiac injuries as well as a rational for the use of MET as a pharmacological preconditioning agent to prevent I/R injuries.


Asunto(s)
Apoptosis/efectos de los fármacos , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Daño por Reperfusión/tratamiento farmacológico , Proteína bcl-X/genética , Animales , Supervivencia Celular/efectos de los fármacos , Humanos , Hipoglucemiantes/farmacología , Metformina/farmacología , Daño por Reperfusión Miocárdica/genética , Daño por Reperfusión Miocárdica/patología , Miocitos Cardíacos/efectos de los fármacos , Ratas , Especies Reactivas de Oxígeno/metabolismo , Daño por Reperfusión/genética , Daño por Reperfusión/patología , Sevoflurano/farmacología , Transducción de Señal/efectos de los fármacos
12.
Proc Natl Acad Sci U S A ; 117(18): 9932-9941, 2020 05 05.
Artículo en Inglés | MEDLINE | ID: mdl-32312819

RESUMEN

Cellular starvation is typically a consequence of tissue injury that disrupts the local blood supply but can also occur where cell populations outgrow the local vasculature, as observed in solid tumors. Cells react to nutrient deprivation by adapting their metabolism, or, if starvation is prolonged, it can result in cell death. Cell starvation also triggers adaptive responses, like angiogenesis, that promote tissue reorganization and repair, but other adaptive responses and their mediators are still poorly characterized. To explore this issue, we analyzed secretomes from glucose-deprived cells, which revealed up-regulation of multiple cytokines and chemokines, including IL-6 and IL-8, in response to starvation stress. Starvation-induced cytokines were cell type-dependent, and they were also released from primary epithelial cells. Most cytokines were up-regulated in a manner dependent on NF-κB and the transcription factor of the integrated stress response ATF4, which bound directly to the IL-8 promoter. Furthermore, glutamine deprivation, as well as the antimetabolic drugs 2-deoxyglucose and metformin, also promoted the release of IL-6 and IL-8. Finally, some of the factors released from starved cells induced chemotaxis of B cells, macrophages, and neutrophils, suggesting that nutrient deprivation in the tumor environment can serve as an initiator of tumor inflammation.


Asunto(s)
Inflamación/genética , Interleucina-6/genética , Interleucina-8/genética , Neoplasias/metabolismo , Estrés Fisiológico/genética , Factor de Transcripción Activador 4/genética , Factor de Transcripción Activador 4/metabolismo , Antimetabolitos/farmacología , Muerte Celular/efectos de los fármacos , Desoxiglucosa/farmacología , Células Epiteliales/metabolismo , Células Epiteliales/patología , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/inmunología , Glucosa/metabolismo , Glutamina/metabolismo , Células HeLa , Humanos , Inflamación/inmunología , Inflamación/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismo , Metformina/farmacología , FN-kappa B/genética , Neoplasias/genética , Regiones Promotoras Genéticas/genética , Inanición/genética , Inanición/metabolismo , Estrés Fisiológico/inmunología
13.
Cell Death Discov ; 6: 22, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32337074

RESUMEN

To address unmet clinical need for uveal melanomas, we assessed the effects of BH3-mimetic molecules, the ABT family, known to exert pro-apoptotic activities in cancer cells. Our results uncovered that ABT-263 (Navitoclax), a potent and orally bioavailable BCL-2 family inhibitor, induced antiproliferative effects in metastatic human uveal melanoma cells through cell cycle arrest at the G0/G1 phase, loss of mitochondrial membrane potential, and subsequently apoptotic cell death monitored by caspase activation and poly-ADP ribose polymerase cleavage. ABT-263-mediated reduction in tumor growth was also observed in vivo. We observed in some cells that ABT-263 treatment mounted a pro-survival response through activation of the ER stress signaling pathway. Blocking the PERK signaling pathway increased the pro-apoptotic ABT-263 effect. We thus uncovered a resistance mechanism in uveal melanoma cells mediated by activation of endoplasmic reticulum stress pathway. Therefore, our study identifies ABT-263 as a valid therapeutic option for patients suffering from uveal melanoma.

14.
Cancer Cell ; 36(3): 268-287.e10, 2019 09 16.
Artículo en Inglés | MEDLINE | ID: mdl-31447347

RESUMEN

GAPDH is emerging as a key player in T cell development and function. To investigate the role of GAPDH in T cells, we generated a transgenic mouse model overexpressing GAPDH in the T cell lineage. Aged mice developed a peripheral Tfh-like lymphoma that recapitulated key molecular, pathological, and immunophenotypic features of human angioimmunoblastic T cell lymphoma (AITL). GAPDH induced non-canonical NF-κB pathway activation in mouse T cells, which was strongly activated in human AITL. We developed a NIK inhibitor to reveal that targeting the NF-κB pathway prolonged AITL-bearing mouse survival alone and in combination with anti-PD-1. These findings suggest the therapeutic potential of targeting NF-κB signaling in AITL and provide a model for future AITL therapeutic investigations.


Asunto(s)
Gliceraldehído-3-Fosfato Deshidrogenasa (Fosforilante)/metabolismo , Linfadenopatía Inmunoblástica/patología , Linfoma de Células T/patología , FN-kappa B/metabolismo , Linfocitos T/inmunología , Anciano , Animales , Línea Celular Tumoral , Linaje de la Célula/inmunología , Conjuntos de Datos como Asunto , Modelos Animales de Enfermedad , Femenino , Técnicas de Silenciamiento del Gen , Gliceraldehído-3-Fosfato Deshidrogenasa (Fosforilante)/genética , Células HEK293 , Humanos , Linfadenopatía Inmunoblástica/genética , Linfoma de Células T/tratamiento farmacológico , Linfoma de Células T/genética , Linfoma de Células T/inmunología , Masculino , Ratones Transgénicos , Persona de Mediana Edad , FN-kappa B/genética , Inhibidores de Proteínas Quinasas/administración & dosificación , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Transducción de Señal/inmunología , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismo , Quinasa de Factor Nuclear kappa B
15.
Cell Metab ; 29(6): 1243-1257.e10, 2019 06 04.
Artículo en Inglés | MEDLINE | ID: mdl-30827861

RESUMEN

Diffuse large B cell lymphoma (DLBCL) is a heterogeneous disease treated with anti-CD20-based immuno-chemotherapy (R-CHOP). We identified that low levels of GAPDH predict a poor response to R-CHOP treatment. Importantly, we demonstrated that GAPDHlow lymphomas use OxPhos metabolism and rely on mTORC1 signaling and glutaminolysis. Consistently, disruptors of OxPhos metabolism (phenformin) or glutaminolysis (L-asparaginase) induce cytotoxic responses in GAPDHlow B cells and improve GAPDHlow B cell-lymphoma-bearing mice survival, while they are low or not efficient on GAPDHhigh B cell lymphomas. Ultimately, we selected four GAPDHlow DLBCL patients, who were refractory to all anti-CD20-based therapies, and targeted DLBCL metabolism using L-asparaginase (K), mTOR inhibitor (T), and metformin (M) (called KTM therapy). Three out of the four patients presented a complete response upon one cycle of KTM. These findings establish that the GAPDH expression level predicts DLBCL patients' response to R-CHOP treatment and their sensitivity to specific metabolic inhibitors.


Asunto(s)
Antimetabolitos Antineoplásicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Gliceraldehído-3-Fosfato Deshidrogenasas/genética , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Animales , Antimetabolitos Antineoplásicos/administración & dosificación , Células Cultivadas , Estudios de Cohortes , Ciclofosfamida/uso terapéutico , Doxorrubicina/uso terapéutico , Femenino , Regulación Enzimológica de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Gliceraldehído-3-Fosfato Deshidrogenasas/metabolismo , Células HEK293 , Humanos , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células B Grandes Difuso/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Persona de Mediana Edad , Prednisona/uso terapéutico , Pronóstico , Estudios Retrospectivos , Rituximab/uso terapéutico , Resultado del Tratamiento , Vincristina/uso terapéutico , Adulto Joven
16.
Leukemia ; 33(6): 1501-1513, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30607021

RESUMEN

Chaperone-mediated autophagy (CMA) is a highly selective form of autophagy. During CMA, the HSC70 chaperone carries target proteins endowed with a KFERQ-like motif to the lysosomal receptor LAMP2A, which then translocate them into lysosomes for degradation. In the present study, we scrutinized the mechanisms underlying the response and resistance to Azacytidine (Aza) in MDS/AML cell lines and bone marrow CD34+ blasts from MDS/AML patients. In engineered Aza-resistant MDS cell lines and some AML cell lines, we identified a profound defect in CMA linked to the absence of LAMP2A. LAMP2 deficiency was responsible for Aza resistance and hypersensitivity to lysosome and autophagy inhibitors. Accordingly, gain of function of LAMP2 in deficient cells or loss of function in LAMP2-expressing cells rendered them sensitive or resistant to Aza, respectively. A strict correlation was observed between the absence of LAMP2, resistance to Aza and sensitivity to lysosome inhibitors. Low levels of LAMP2 expression in CD34+ blasts from MDS/AML patients correlated with lack of sensitivity to Aza and were predictive of poor overall survival. We propose that CD34+/LAMP2Low patients at diagnosis or who become CD34+/LAMP2Low during the course of treatment with Aza might benefit from a lysosome inhibitor already used in the clinic.


Asunto(s)
Antimetabolitos Antineoplásicos/farmacología , Azacitidina/farmacología , Biomarcadores de Tumor/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Leucemia Mieloide Aguda/patología , Proteína 2 de la Membrana Asociada a los Lisosomas/metabolismo , Anciano , Anciano de 80 o más Años , Apoptosis , Biomarcadores de Tumor/genética , Proliferación Celular , Femenino , Estudios de Seguimiento , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/metabolismo , Proteína 2 de la Membrana Asociada a los Lisosomas/genética , Masculino , Persona de Mediana Edad , Pronóstico , Tasa de Supervivencia , Células Tumorales Cultivadas
17.
J Invest Dermatol ; 139(6): 1306-1317, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30571969

RESUMEN

Inflammatory caspases, activated within the inflammasome, are responsible for the maturation and secretion of IL-1ß/IL-18. Although their expression in psoriasis was shown several years ago, little is known about the role of inflammatory caspases in the context of psoriasis. Here, we confirmed that caspases 1, 4, and 5 are activated in lesional skin from psoriasis patients. We showed in three psoriasis-like models that inflammatory caspases are activated, and accordingly, caspase 1/11 invalidation or pharmacological inhibition by Ac-YVAD-CMK (i.e., Ac-Tyr-Val-Ala-Asp-chloromethylketone) injection induced a decrease in ear thickness, erythema, scaling, inflammatory cytokine expression, and immune cell infiltration in mice. We observed that keratinocytes were primed to secrete IL-1ß when cultured in conditions mimicking psoriasis. Generation of chimeric mice by bone marrow transplantation was carried out to decipher the respective contribution of keratinocytes and/or immune cells in the activation of inflammatory caspases during psoriasis-like inflammatory response. Our data showed that the presence of caspase 1/11 in the immune system is sufficient for a fully inflammatory response, whereas the absence of caspase 1/11 in keratinocytes/fibroblasts had no impact. In summary, our study indicates that inflammatory caspases activated in immune cells are implicated in psoriasis pathogenesis.


Asunto(s)
Caspasa 1/deficiencia , Inhibidores de Caspasas/administración & dosificación , Caspasas Iniciadoras/deficiencia , Psoriasis/tratamiento farmacológico , Clorometilcetonas de Aminoácidos/administración & dosificación , Animales , Biopsia , Trasplante de Médula Ósea , Caspasa 1/genética , Caspasa 1/inmunología , Caspasas Iniciadoras/genética , Caspasas Iniciadoras/inmunología , Caspasas Iniciadoras/metabolismo , Células Cultivadas , Ensayos Clínicos como Asunto , Femenino , Humanos , Inyecciones Intraperitoneales , Interleucina-1beta/inmunología , Interleucina-1beta/metabolismo , Queratinocitos , Masculino , Ratones , Ratones Noqueados , Cultivo Primario de Células , Psoriasis/inmunología , Psoriasis/patología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Piel/inmunología , Piel/patología , Quimera por Trasplante
18.
Trends Cell Biol ; 28(11): 882-895, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-30115557

RESUMEN

Mitochondria are essential highly dynamic organelles that provide the necessary energy for a variety of different processes, such as survival, proliferation, and migration. In order to maintain an intact mitochondrial network, cells have developed quality control systems that allow the removal of damaged or superfluous mitochondria by selective mitochondrial autophagy called mitophagy. Although the parkin/PINK1 axis is often considered the main regulator of mitophagy, a growing body of evidence has shown that this pathway is not unique and that mitophagy can still be functional in the absence of parkin. Here, we will review recent literature describing parkin-independent mitophagy and its role in various physiopathological conditions, therefore representing potential new targets to treat diseases affected by dysregulated mitophagy.


Asunto(s)
Mitocondrias/metabolismo , Mitofagia , Ubiquitina-Proteína Ligasas , Animales , Humanos , Ubiquitina-Proteína Ligasas/deficiencia , Ubiquitina-Proteína Ligasas/metabolismo
19.
Oncotarget ; 9(13): 10920-10933, 2018 Feb 16.
Artículo en Inglés | MEDLINE | ID: mdl-29541386

RESUMEN

Polo-like kinases (Plks) define a highly conserved family of Ser/Thr kinases with crucial roles in the regulation of cell division. Here we show that Plk1 is cleaved by caspase 3, but not by other caspases in different hematopoietic cell lines treated with competitive inhibitors of the ATP-binding pocket of Plk1. Intriguingly, Plk1 was not cleaved in cells treated with Rigosertib, a non-competitive inhibitor of Plk1, suggesting that binding of the inhibitor to the ATP binding pocket of Plk1 triggers a conformational change and unmasks a cryptic caspase 3 cleavage site on the protein. Cleavage occurs after Asp-404 in a DYSD/K sequence and separates the kinase domain from the two PBDs of Plk1. All Plk1 inhibitors triggered G2/M arrest, activation of caspases 2 and 3, polyploidy, multiple nuclei and mitotic catastrophe, albeit at higher concentrations in the case of Rigosertib. Upon BI-2536 treatment, Plk1 cleavage occurred only in the cytosolic fraction and cleaved Plk1 accumulated in this subcellular compartment. Importantly, the cleaved N-Terminal fragment of Plk1 exhibited a higher enzymatic activity than its non-cleaved counterpart and accumulated into the cytoplasm conversely to the full length and the C-Terminal Plk1 fragments that were found essentially into the nucleus. Finally, the DYSD/K cleavage site was highly conserved during evolution from c. elegans to human. In conclusion, we described herein for the first time a specific cleavage of Plk1 by caspase 3 following treatment of cancer cells with ATP-competitive inhibitors of Plk1.

20.
Cell Metab ; 27(4): 828-842.e7, 2018 04 03.
Artículo en Inglés | MEDLINE | ID: mdl-29551590

RESUMEN

Dietary restriction (DR) was shown to impact on tumor growth with very variable effects depending on the cancer type. However, how DR limits cancer progression remains largely unknown. Here, we demonstrate that feeding mice a low-protein (Low PROT) isocaloric diet but not a low-carbohydrate (Low CHO) diet reduced tumor growth in three independent mouse cancer models. Surprisingly, this effect relies on anticancer immunosurveillance, as depleting CD8+ T cells, antigen-presenting cells (APCs), or using immunodeficient mice prevented the beneficial effect of the diet. Mechanistically, we established that a Low PROT diet induces the unfolded protein response (UPR) in tumor cells through the activation of IRE1α and RIG1 signaling, thereby resulting in cytokine production and mounting an efficient anticancer immune response. Collectively, our data suggest that a Low PROT diet induces an IRE1α-dependent UPR in cancer cells, enhancing a CD8-mediated T cell response against tumors.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Dieta con Restricción de Proteínas , Endorribonucleasas/metabolismo , Vigilancia Inmunológica , Neoplasias Experimentales/dietoterapia , Neoplasias Experimentales/inmunología , Proteínas Serina-Treonina Quinasas/metabolismo , Respuesta de Proteína Desplegada/inmunología , Animales , Células Presentadoras de Antígenos/inmunología , Línea Celular Tumoral , Neoplasias Colorrectales/dietoterapia , Neoplasias Colorrectales/inmunología , Endorribonucleasas/genética , Femenino , Depleción Linfocítica , Linfoma/dietoterapia , Linfoma/inmunología , Melanoma Experimental/dietoterapia , Melanoma Experimental/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Proteínas Serina-Treonina Quinasas/genética , ARN Helicasas/metabolismo , Transducción de Señal
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