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Cellular senescence has been increasingly recognized as a hallmark of cancer, reflecting its association with aging and inflammation, its role as a response to deregulated proliferation and oncogenic stress, and its induction by cancer therapies. While therapy-induced senescence (TIS) has been linked to resistance, recurrence, metastasis, and normal tissue toxicity, TIS also has the potential to enhance therapy response and stimulate anti-tumor immunity. In this review, we examine the Jekyll and Hyde nature of senescent cells (SnCs), focusing on how their persistence while expressing the senescence-associated secretory phenotype (SASP) modulates the tumor microenvironment through autocrine and paracrine mechanisms. Through the SASP, SnCs can mediate both resistance and response to cancer therapies. To fulfill the unmet potential of cancer immunotherapy, we consider how SnCs may influence tumor inflammation and serve as an antigen source to potentiate anti-tumor immune response. This new perspective suggests treatment approaches based on TIS to enhance immune checkpoint blockade. Finally, we describe strategies for mitigating the detrimental effects of senescence, such as modulating the SASP or targeting SnC persistence, which may enhance the overall benefits of cancer treatment.
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Senescencia Celular , Resistencia a Antineoplásicos , Neoplasias , Humanos , Neoplasias/patología , Neoplasias/inmunología , Microambiente Tumoral/inmunología , Fenotipo Secretor Asociado a la Senescencia , Animales , Inmunoterapia/métodos , Recurrencia Local de Neoplasia/inmunología , Recurrencia Local de Neoplasia/patologíaRESUMEN
Autophagy is known to suppress tumor initiation by removing genotoxic stresses in normal cells. Conversely, autophagy is also known to support tumor progression by alleviating metabolic stresses in neoplastic cells. Centered on this pro-tumor role of autophagy, there have been many clinical trials to treat cancers through systemic blocking of autophagy. Such systemic inhibition affects both tumor cells and non-tumor cells, and the consequence of blocked autophagy in non-tumor cells in the context of tumor microenvironment is relatively understudied. Here, we examined the effect of autophagy-deficient myeloid cells on the progression of autophagy-competent tumors. We found that blocking autophagy only in myeloid cells modulated tumor progression markedly but such effects were context dependent. In a tumor implantation model, the growth of implanted tumor cells was substantially reduced in mice with autophagy-deficient myeloid cells; T cells infiltrated deeper into the tumors and were responsible for the reduced growth of the implanted tumor cells. In an oncogene-driven tumor induction model, however, tumors grew faster and metastasized more in mice with autophagy-deficient myeloid cells. These data demonstrate that the autophagy status of myeloid cells plays a critical role in tumor progression, promoting or suppressing tumor growth depending on the context of tumor-myeloid cell interactions. This study indicates that systemic use of autophagy inhibitors in cancer therapy may have differential effects on rates of tumor progression in patients due to effects on myeloid cells and that this warrants more targeted use of selective autophagy inhibitors in a cancer therapy in a clinical setting.
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CUX1 is a homeodomain-containing transcription factor that is essential for the development and differentiation of multiple tissues. CUX1 is recurrently mutated or deleted in cancer, particularly in myeloid malignancies. However, the mechanism by which CUX1 regulates gene expression and differentiation remains poorly understood, creating a barrier to understanding the tumor-suppressive functions of CUX1. Here, we demonstrate that CUX1 directs the BAF chromatin remodeling complex to DNA to increase chromatin accessibility in hematopoietic cells. CUX1 preferentially regulates lineage-specific enhancers, and CUX1 target genes are predictive of cell fate in vivo. These data indicate that CUX1 regulates hematopoietic lineage commitment and homeostasis via pioneer factor activity, and CUX1 deficiency disrupts these processes in stem and progenitor cells, facilitating transformation.
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Cromatina , Células Madre Hematopoyéticas , Proteínas de Homeodominio , Proteínas Represoras , Humanos , Proteínas de Homeodominio/metabolismo , Proteínas de Homeodominio/genética , Células Madre Hematopoyéticas/metabolismo , Células Madre Hematopoyéticas/citología , Cromatina/metabolismo , Proteínas Represoras/metabolismo , Proteínas Represoras/genética , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Animales , Ratones , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Linaje de la Célula , Ensamble y Desensamble de Cromatina , Diferenciación Celular , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , Elementos de Facilitación Genéticos/genéticaRESUMEN
Therapy-induced senescence (TIS) may contribute to therapy resistance; however, evidence also suggests that senescent cells (SnCs) may promote anti-tumor immunity. Here, we present a protocol for examining the capability of TIS to stimulate type 1 conventional CD103+ dendritic cells (DCs). We describe steps for isolating and differentiating CD103+ DCs from murine bone marrow, inducing senescence in murine colon carcinoma cell line CT26, and coculturing DCs with SnCs. We then detail the flow cytometric analysis of DC maturation and activation. For complete details on the use and execution of this protocol, please refer to Liu et al. (2022)1 and Liu et al. (2023).2.
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Neoplasias del Colon , Células Dendríticas , Animales , Ratones , Citometría de Flujo , Médula Ósea/patología , Neoplasias del Colon/patología , Células CultivadasRESUMEN
Statins, a class of HMG-CoA reductase inhibitors best known for their cholesterol-reducing and cardiovascular protective activity, have also demonstrated promise in cancer prevention and treatment. This review focuses on their potential applications in head and neck cancer (HNC), a common malignancy for which established treatment often fails despite incurring debilitating adverse effects. Preclinical and clinical studies have suggested that statins may enhance HNC sensitivity to radiation and other conventional therapies while protecting normal tissue, but the underlying mechanisms remain poorly defined, likely involving both cholesterol-dependent and -independent effects on diverse cancer-related pathways. This review brings together recent discoveries concerning the anticancer activity of statins relevant to HNC, highlighting their anti-inflammatory activity and impacts on DNA-damage response. We also explore molecular targets and mechanisms and discuss the potential to integrate statins into conventional HNC treatment regimens to improve patient outcomes.
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BACKGROUND: Immune tolerance contributes to resistance to conventional cancer therapies such as radiation. Radiotherapy induces immunogenic cell death, releasing a burst of tumor antigens, but this appears insufficient to stimulate an effective antitumor immune response. Radiation also increases infiltration of cytotoxic T lymphocytes (CTLs), but their effector function is short lived. Although CTL exhaustion may be at fault, combining immune checkpoint blockade with radiation is insufficient to restore CTL function in most patients. An alternative model is that antigen presentation is the limiting factor, suggesting a defect in dendritic cell (DC) function. METHODS: Building on our prior work showing that cancer cells treated with radiation in the presence of the poly(ADP-ribose) polymerase-1 inhibitor veliparib undergo immunogenic senescence, we reexamined senescent cells (SnCs) as preventative or therapeutic cancer vaccines. SnCs formed in vitro were cocultured with splenocytes and evaluated by scRNA-seq to examine immunogenicity. Immature bone-marrow-derived DCs cocultured with SnCs were examined for maturation and activation by flow cytometry and T cell proliferation assays. Viable SnCs or SnC-activated DCs were injected subcutaneously, and vaccine effects were evaluated by analysis of immune response, prevention of tumor engraftment, regression of established tumors and/or potentiation of immunotherapy or radiotherapy. RESULTS: Murine CT26 colon carcinoma or 4T1 mammary carcinoma cells treated with radiation and veliparib form SnCs that promote DC maturation and activation in vitro, leading to efficient, STING-dependent CTL priming. Injecting mice with SnCs induces antigen-specific CTLs and confers protection from tumor engraftment. Injecting immunogenic SnCs into tumor-bearing mice increases inflammation with activated CTLs, suppresses tumor growth, potentiates checkpoint blockade, enhances radiotherapy and blocks colonization by disseminated tumor cells. Addressing the concern that reinjecting tumor cells into patients may be impractical, DCs activated with SnCs in vitro were similarly effective to SnCs in suppressing established tumors and blocking metastases. CONCLUSIONS: Therapeutic vaccines based on senescent tumor cells and/or SnC-activated DCs have the potential to improve genotoxic and immune therapies and limit recurrence or metastasis.
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Vacunas contra el Cáncer , Carcinoma , Neoplasias del Colon , Ratones , Animales , Linfocitos T Citotóxicos , Antígenos de Neoplasias , Carcinoma/tratamiento farmacológicoRESUMEN
Sorting transmembrane cargo is essential for tissue development and homeostasis. However, mechanisms of intracellular trafficking in stratified epidermis are poorly understood. Here, we identify an interaction between the retromer endosomal trafficking component, VPS35, and the desmosomal cadherin, desmoglein-1 (Dsg1). Dsg1 is specifically expressed in stratified epidermis and, when properly localized on the plasma membrane of basal keratinocytes, promotes stratification. We show that the retromer drives Dsg1 recycling from the endo-lysosomal system to the plasma membrane to support human keratinocyte stratification. The retromer-enhancing chaperone, R55, promotes the membrane localization of Dsg1 and a trafficking-deficient mutant associated with a severe inflammatory skin disorder, enhancing its ability to promote stratification. In the absence of Dsg1, retromer association with and expression of the glucose transporter GLUT1 increases, exposing a potential link between Dsg1 deficiency and epidermal metabolism. Our work provides evidence for retromer function in epidermal regeneration, identifying it as a potential therapeutic target.
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Desmogleína 1 , Epidermis , Humanos , Cadherinas/metabolismo , Desmogleína 1/metabolismo , Endosomas/metabolismo , Células Epidérmicas/metabolismo , Epidermis/metabolismo , Queratinocitos/metabolismoRESUMEN
Beyond synthesizing telomere repeats, the telomerase reverse transcriptase (TERT) also serves multiple other roles supporting cancer growth. Blocking telomerase to drive telomere erosion appears impractical, but TERT's non-canonical activities have yet to be fully explored as cancer targets. Here, we used an irreversible TERT inhibitor, NU-1, to examine impacts on resistance to conventional cancer therapies. In vitro, inhibiting TERT sensitized cells to chemotherapy and radiation. NU-1 delayed repair of double-strand breaks, resulting in persistent DNA damage signaling and cellular senescence. Although NU-1 alone did not impact growth of syngeneic CT26 tumors in BALB/c mice, it dramatically enhanced the effects of radiation, leading to immune-dependent tumor elimination. Tumors displayed persistent DNA damage, suppressed proliferation, and increased activated immune infiltrate. Our studies confirm TERT's role in limiting genotoxic effects of conventional therapy but also implicate TERT as a determinant of immune evasion and therapy resistance.
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Tolerancia a Radiación , Telomerasa , Animales , Ratones , Senescencia Celular/efectos de los fármacos , Daño del ADN/efectos de los fármacos , Tolerancia a Radiación/efectos de los fármacos , Telomerasa/antagonistas & inhibidores , Telomerasa/metabolismo , TelómeroRESUMEN
Somatic MEN1 mutations occur in up to 50% of pancreatic neuroendocrine tumors (PanNETs). Clinical studies have shown that radiation therapy (IR) is effective in a subset of PanNETs, but it remains unclear why some patients respond better to IR than others. Herein, we study whether MEN1 loss of function increases radiosensitivity of PanNETs and determine its effect on DNA double-strand break (DSB) repair. After creating a MEN1 knockout PanNET cell line, we confirmed reduced DSB repair capacity in MEN1-deficient cells and linked these findings to a defect in homologous recombination, as well as reduced BRCA2 expression levels. Consistent with this model, we found that MEN1 mutant cells displayed increased sensitivity to the highly trapping poly (ADP-ribose) polymerase (PARP) 1 inhibitor talazoparib in vitro. Our results suggest that combining IR with PARP inhibition may be beneficial in patients with PanNETs and MEN1 loss of function.
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Tumores Neuroendocrinos , Neoplasias Pancreáticas , Proteínas Proto-Oncogénicas/metabolismo , Reparación del ADN , Humanos , Tumores Neuroendocrinos/patología , Neoplasias Pancreáticas/patología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Poli(ADP-Ribosa) Polimerasas/metabolismoRESUMEN
CUX1, encoding a homeodomain-containing transcription factor, is recurrently deleted or mutated in multiple tumor types. In myeloid neoplasms, CUX1 deletion or mutation carries a poor prognosis. We have previously established that CUX1 functions as a tumor suppressor in hematopoietic cells across multiple organisms. Others, however, have described oncogenic functions of CUX1 in solid tumors, often attributed to truncated CUX1 isoforms, p75 and p110, generated by an alternative transcriptional start site or post-translational cleavage, respectively. Given the clinical relevance, it is imperative to clarify these discrepant activities. Herein, we sought to determine the CUX1 isoforms expressed in hematopoietic cells and find that they express the full-length p200 isoform. Through the course of this analysis, we found no evidence of the p75 alternative transcript in any cell type examined. Using an array of orthogonal approaches, including biochemistry, proteomics, CRISPR/Cas9 genomic editing, and analysis of functional genomics datasets across a spectrum of normal and malignant tissue types, we found no data to support the existence of the CUX1 p75 isoform as previously described. Based on these results, prior studies of p75 require reevaluation, including the interpretation of oncogenic roles attributed to CUX1.
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Genómica , Células Madre Hematopoyéticas/metabolismo , Proteínas de Homeodominio/genética , Proteínas Represoras/genética , Factores de Transcripción/genética , Animales , Células HL-60 , Proteínas de Homeodominio/metabolismo , Humanos , Células K562 , Células MCF-7 , Ratones , Células 3T3 NIH , Isoformas de Proteínas , Procesamiento Postranscripcional del ARN , Proteínas Represoras/metabolismo , Factores de Transcripción/metabolismo , Sitio de Iniciación de la Transcripción , Transcripción Genética , Activación Transcripcional , Células U937RESUMEN
The genome of a living cell is continuously damaged by various exogenous and endogenous factors yielding multiple types of DNA damage including base damage and damage to the sugar-phosphate backbone of DNA. Double Strand Breaks (DSBs) are the most severe form of DNA damage and if left unchecked, may precipitate genomic rearrangements, cell death or contribute to malignancy. In clinical contexts, radiation is often used to induce DSBs as a form of genotoxic therapy. Despite the importance of DSBs and their repair, as yet there is no facile assay to detect DSBs in situ or to quantify their location or proximity to other cellular constituents. Such an assay would help to disentangle DDR signaling pathways and identify new molecular players involved in DSB repair. These efforts, in turn, may facilitate drug screening and accelerate the discovery of novel, more effective genotoxic agents. We have developed such an assay, presented here, and term it TdT-dUTP DSB End Labeling (TUDEL).TUDEL makes use of Terminal Deoxynucleotidyl Transferase (TdT), a template-independent DNA polymerase. TdT is commonly used in TUNEL assays to yield a binary output of DNA damage. We have adapted this approach, using TdT and EdUTP to label individual DNA double strand breaks in irradiated cells and detecting the incorporated EdU with fluorescent probes via Click chemistry. This tool complements and is compatible with existing, indirect methods to track DSBs such as immunofluorescent detection of γH2AX. TUDEL is also sufficiently specific, sensitive, quantitative, and robust to replace the neutral Comet assay for routine measurement of DSB formation and repair. Here we present a protocol for TUDEL.
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Roturas del ADN de Doble Cadena , ADN Nucleotidilexotransferasa , ADN/genética , Daño del ADN , Reparación del ADN , ADN Polimerasa Dirigida por ADNRESUMEN
The plant pathogen Pseudomonas syringae secretes multiple effectors that modulate plant defenses. Some effectors trigger defenses due to specific recognition by plant immune complexes, whereas others can suppress the resulting immune responses. The HopZ3 effector of P. syringae pv. syringae B728a (PsyB728a) is an acetyltransferase that modifies not only components of plant immune complexes, but also the Psy effectors that activate these complexes. In Arabidopsis, HopZ3 acetylates the host RPM1 complex and the Psy effectors AvrRpm1 and AvrB3. This study focuses on the role of HopZ3 during tomato infection. In Psy-resistant tomato, the main immune complex includes PRF and PTO, a RIPK-family kinase that recognizes the AvrPto effector. HopZ3 acts as a virulence factor on tomato by suppressing AvrPto1Psy-triggered immunity. HopZ3 acetylates AvrPto1Psy and the host proteins PTO, SlRIPK and SlRIN4s. Biochemical reconstruction and site-directed mutagenesis experiments suggest that acetylation acts in multiple ways to suppress immune signaling in tomato. First, acetylation disrupts the critical AvrPto1Psy-PTO interaction needed to initiate the immune response. Unmodified residues at the binding interface of both proteins and at other residues needed for binding are acetylated. Second, acetylation occurs at residues important for AvrPto1Psy function but not for binding to PTO. Finally, acetylation reduces specific phosphorylations needed for promoting the immune-inducing activity of HopZ3's targets such as AvrPto1Psy and PTO. In some cases, acetylation competes with phosphorylation. HopZ3-mediated acetylation suppresses the kinase activity of SlRIPK and the phosphorylation of its SlRIN4 substrate previously implicated in PTO-signaling. Thus, HopZ3 disrupts the functions of multiple immune components and the effectors that trigger them, leading to increased susceptibility to infection. Finally, mass spectrometry used to map specific acetylated residues confirmed HopZ3's unusual capacity to modify histidine in addition to serine, threonine and lysine residues.
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Acetiltransferasas/metabolismo , Complejo Antígeno-Anticuerpo/inmunología , Proteínas Bacterianas/antagonistas & inhibidores , Enfermedades de las Plantas/inmunología , Proteínas de Plantas/metabolismo , Pseudomonas syringae/patogenicidad , Solanum lycopersicum/inmunología , Acetilación , Acetiltransferasas/genética , Acetiltransferasas/inmunología , Proteínas Bacterianas/genética , Proteínas Bacterianas/inmunología , Proteínas Bacterianas/metabolismo , Solanum lycopersicum/microbiología , Enfermedades de las Plantas/microbiología , Proteínas de Plantas/genética , Proteínas de Plantas/inmunología , Virulencia , Factores de Virulencia/genética , Factores de Virulencia/inmunología , Factores de Virulencia/metabolismoRESUMEN
Polyphosphate (polyP) is a polymer of hundreds of phosphate residues present in all organisms. In mammals, polyP is involved in crucial physiological processes, including coagulation, inflammation, and stress response. However, after decades of research, the metabolic enzymes are still unknown. Here, we purify and identify Nudt3, a NUDIX family member, as the enzyme responsible for polyP phosphatase activity in mammalian cells. We show that Nudt3 shifts its substrate specificity depending on the cation; specifically, Nudt3 is active on polyP when Zn2+ is present. Nudt3 has in vivo polyP phosphatase activity in human cells, and importantly, we show that cells with altered polyP levels by modifying Nudt3 protein amount present reduced viability upon oxidative stress and increased DNA damage, suggesting that polyP and Nudt3 play a role in oxidative stress protection. Finally, we show that Nudt3 is involved in the early stages of embryo development in zebrafish.
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Ácido Anhídrido Hidrolasas/metabolismo , Estrés Oxidativo/fisiología , Polifosfatos/metabolismo , Ácido Anhídrido Hidrolasas/genética , Ácido Anhídrido Hidrolasas/fisiología , Animales , Células HEK293 , Humanos , Masculino , Mamíferos/metabolismo , Oxidación-Reducción , Monoéster Fosfórico Hidrolasas/fisiología , Ratas , Ratas Sprague-Dawley , Especificidad por Sustrato/fisiología , Pez Cebra , Zinc/metabolismoRESUMEN
Therapy-related myeloid neoplasms (t-MNs) are high-risk late effects with poorly understood pathogenesis in cancer survivors. It has been postulated that, in some cases, hematopoietic stem and progenitor cells (HSPCs) harboring mutations are selected for by cytotoxic exposures and transform. Here, we evaluate this model in the context of deficiency of CUX1, a transcription factor encoded on chromosome 7q and deleted in half of t-MN cases. We report that CUX1 has a critical early role in the DNA repair process in HSPCs. Mechanistically, CUX1 recruits the histone methyltransferase EHMT2 to DNA breaks to promote downstream H3K9 and H3K27 methylation, phosphorylated ATM retention, subsequent γH2AX focus formation and propagation, and, ultimately, 53BP1 recruitment. Despite significant unrepaired DNA damage sustained in CUX1-deficient murine HSPCs after cytotoxic exposures, they continue to proliferate and expand, mimicking clonal hematopoiesis in patients postchemotherapy. As a consequence, preexisting CUX1 deficiency predisposes mice to highly penetrant and rapidly fatal therapy-related erythroleukemias. These findings establish the importance of epigenetic regulation of HSPC DNA repair and position CUX1 as a gatekeeper in myeloid transformation.
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Cromosomas de los Mamíferos , Reparación del ADN , Epigénesis Genética , Regulación Leucémica de la Expresión Génica , Proteínas de Homeodominio , Leucemia Eritroblástica Aguda , Proteínas de Neoplasias , Neoplasias Primarias Secundarias , Proteínas Nucleares , Proteínas Represoras , Animales , Cromosomas de los Mamíferos/genética , Cromosomas de los Mamíferos/metabolismo , Hematopoyesis Clonal , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Leucemia Eritroblástica Aguda/genética , Leucemia Eritroblástica Aguda/metabolismo , Ratones , Ratones Transgénicos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias Primarias Secundarias/genética , Neoplasias Primarias Secundarias/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas Represoras/genética , Proteínas Represoras/metabolismoRESUMEN
Multiplexed tissue tomography enables comprehensive spatial analysis of markers within a whole tissue or thick tissue section. Clearing agents are often used to make tissue transparent and facilitate deep tissue imaging. Many methods of clearing and tissue tomography are currently used in a variety of tissue types. Here we detail a workflow known as transparent tissue tomography (T3), which builds upon previous methods and can be applied to difficult to clear tissues such as tumors.
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Técnica del Anticuerpo Fluorescente , Histocitoquímica/métodos , Imagen Óptica/métodos , Tomografía/métodos , Animales , Biomarcadores , Humanos , Imagenología Tridimensional/métodos , Ratones , Especificidad de Órganos , Flujo de TrabajoRESUMEN
The UltraPlex method for multiplexed two-dimensional fluorescent immunohistochemistry is described, in which hapten tags conjugated to primary antibodies facilitate multiplexed imaging of four or more antigens per tissue section at once. Anti-hapten secondary antibodies labeled with fluorophores provide amplified signal for detection, which is accomplished using a standard fluorescent microscope or digital slide scanner. The protocol is rapid and straightforward and utilizes conventionally prepared tissue samples. The resulting staining is highly sensitive and specific, enabling high-resolution imaging of multiple cellular subtypes within tissue samples. Tumor cells and tumor-infiltrating lymphocytes are presented as examples. Multiple 4-plex-stained tissue samples can be digitally overlaid to create 8-plex (or more) high-content images, enabling visualization of distribution of complex cellular subtypes across tissues.
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Técnica del Anticuerpo Fluorescente , Haptenos , Inmunohistoquímica/métodos , Biomarcadores , Biomarcadores de Tumor , Análisis de Datos , Humanos , Procesamiento de Imagen Asistido por Computador/métodos , Neoplasias/metabolismo , Neoplasias/patología , Coloración y EtiquetadoRESUMEN
Sphingosine-1-phosphate (S1P), a bioactive lipid mediator, is generated from sphingosine by sphingosine kinases (SPHKs) 1 and 2 and is metabolized to ∆2-hexadecenal (∆2-HDE) and ethanolamine phosphate by S1P lyase (S1PL) in mammalian cells. We have recently demonstrated the activation of nuclear SPHK2 and the generation of S1P in the nucleus of lung epithelial cells exposed to Pseudomonas aeruginosa. Here, we have investigated the nuclear localization of S1PL and the role of ∆2-HDE generated from S1P in the nucleus as a modulator of histone deacetylase (HDAC) activity and histone acetylation. Electron micrographs of the nuclear fractions isolated from MLE-12 cells showed nuclei free of ER contamination, and S1PL activity was detected in nuclear fractions isolated from primary lung bronchial epithelial cells and alveolar epithelial MLE-12 cells. Pseudomonas aeruginosa-mediated nuclear ∆2-HDE generation, and H3/H4 histone acetylation was attenuated by S1PL inhibitors in MLE-12 cells and human bronchial epithelial cells. In vitro, the addition of exogenous ∆2-HDE (100-10,000 nM) to lung epithelial cell nuclear preparations inhibited HDAC1/2 activity, and increased acetylation of Histone H3 and H4, whereas similar concentrations of S1P did not show a significant change. In addition, incubation of ∆2-HDE with rHDAC1 generated five different amino acid adducts as detected by LC-MS/MS; the predominant adduct being ∆2-HDE with lysine residues of HDAC1. Together, these data show an important role for the nuclear S1PL-derived ∆2-HDE in the modification of HDAC activity, histone acetylation, and chromatin remodeling in lung epithelial cells.
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Aldehído-LiasasRESUMEN
Cellular senescence is an essential tumor suppressive mechanism that prevents the propagation of oncogenically activated, genetically unstable, and/or damaged cells. Induction of tumor cell senescence is also one of the underlying mechanisms by which cancer therapies exert antitumor activity. However, an increasing body of evidence from preclinical studies demonstrates that radiation and chemotherapy cause accumulation of senescent cells (SnCs) both in tumor and normal tissue. SnCs in tumors can, paradoxically, promote tumor relapse, metastasis, and resistance to therapy, in part, through expression of the senescence-associated secretory phenotype. In addition, SnCs in normal tissue can contribute to certain radiation- and chemotherapy-induced side effects. Because of its multiple roles, cellular senescence could serve as an important target in the fight against cancer. This commentary provides a summary of the discussion at the National Cancer Institute Workshop on Radiation, Senescence, and Cancer (August 10-11, 2020, National Cancer Institute, Bethesda, MD) regarding the current status of senescence research, heterogeneity of therapy-induced senescence, current status of senotherapeutics and molecular biomarkers, a concept of "one-two punch" cancer therapy (consisting of therapeutics to induce tumor cell senescence followed by selective clearance of SnCs), and its integration with personalized adaptive tumor therapy. It also identifies key knowledge gaps and outlines future directions in this emerging field to improve treatment outcomes for cancer patients.
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Senescencia Celular , Neoplasias , Biomarcadores , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Fenotipo Secretor Asociado a la SenescenciaRESUMEN
For decades genotoxic therapy has been a mainstay in the treatment of cancer, based on the understanding that the deregulated growth and genomic instability that drive malignancy also confer a shared vulnerability. Although chemotherapy and radiation can be curative, only a fraction of patients benefit, while nearly all are subjected to the harmful side-effects. Drug repurposing, defined here as retooling existing drugs and compounds as chemo or radiosensitizers, offers an attractive route to identifying otherwise non-toxic agents that can potentiate the benefits of genotoxic cancer therapy to enhance the therapeutic ratio. This review seeks to highlight recent progress in defining cellular mechanisms of the DNA damage response including damage sensing, chromatin modification, DNA repair, checkpoint signaling, and downstream survival and death pathways, as a framework to determine which drugs and natural products may offer the most potential for repurposing as chemo- and/or radiosensitizers. We point to classical examples and recent progress that have identified drugs that disrupt cellular responses to DNA damage and may offer the greatest clinical potential. The most important next steps may be to initiate prospective clinical trials toward translating these laboratory discoveries to benefit patients.
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Antineoplásicos/uso terapéutico , Enzimas Reparadoras del ADN/antagonistas & inhibidores , Descubrimiento de Drogas , Reposicionamiento de Medicamentos/métodos , Neoplasias/tratamiento farmacológico , Bibliotecas de Moléculas Pequeñas/uso terapéutico , Animales , Daño del ADN , Reparación del ADN , HumanosRESUMEN
Cells exposed to heat shock induce a conserved gene expression program, the heat shock response (HSR), encoding protein homeostasis (proteostasis) factors. Heat shock also triggers proteostasis factors to form subcellular quality control bodies, but the relationship between these spatial structures and the HSR is unclear. Here we show that localization of the J-protein Sis1, a cofactor for the chaperone Hsp70, controls HSR activation in yeast. Under nonstress conditions, Sis1 is concentrated in the nucleoplasm, where it promotes Hsp70 binding to the transcription factor Hsf1, repressing the HSR. Upon heat shock, Sis1 forms an interconnected network with other proteostasis factors that spans the nucleolus and the surface of the endoplasmic reticulum. We propose that localization of Sis1 to this network directs Hsp70 activity away from Hsf1 in the nucleoplasm, leaving Hsf1 free to induce the HSR. In this manner, Sis1 couples HSR activation to the spatial organization of the proteostasis network.