Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 7 de 7
Filtrar
Más filtros












Base de datos
Intervalo de año de publicación
1.
Cardiooncology ; 10(1): 56, 2024 Sep 04.
Artículo en Inglés | MEDLINE | ID: mdl-39232830

RESUMEN

BACKGROUND: Cardiovascular toxicity represents a significant adverse consequence of cancer therapies, yet there remains a paucity of effective biomarkers for its timely monitoring and diagnosis. To give a first evidence able to elucidate the role of Growth Differentiation Factor 15 (GDF15) in the context of cancer diagnosis and its specific association with cardiac indicators in cancer patients, thereby testing its potential in predicting the risk of CTRCD (cancer therapy related cardiac dysfunction). METHODS: Analysis of differentially expressed genes (DEGs), including GDF15, was performed by utilizing data from the public repositories of the Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO). Cardiomyopathy is the most common heart disease and its main clinical manifestations, such as heart failure and arrhythmia, are similar to those of CTRCD. Examination of GDF15 expression was conducted in various normal and cancerous tissues or sera, using available database and serum samples. The study further explored the correlation between GDF15 expression and the combined detection of cardiac troponin-T (c-TnT) and N-terminal prohormone of brain natriuretic peptide (NT-proBNP), assessing the combined diagnostic utility of these markers in predicting risk of CTRCD through longitudinal electrocardiograms (ECG). RESULTS: GDF15 emerged as a significant DEG in both cancer and cardiomyopathy disease models, demonstrating good diagnostic efficacy across multiple cancer types compared to healthy controls. GDF15 levels in cancer patients correlated with the established cardiac biomarkers c-TnT and NT-proBNP. Moreover, higher GDF15 levels correlated with an increased risk of ECG changes in the cancer cohort. CONCLUSION: GDF15 demonstrated promising diagnostic potential in cancer identification; higher GDF15, combined with elevated cardiac markers, may play a role in the monitoring and prediction of CTRCD risk.

2.
Oncogene ; 41(3): 427-443, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34773075

RESUMEN

Reactive oxygen species (ROS) serve as critical signals in various cellular processes. Excessive ROS cause cell death or senescence and mediates the therapeutic effect of many cancer drugs. Recent studies showed that ROS increasingly accumulate during G2/M arrest, the underlying mechanism, however, has not been fully elucidated. Here, we show that in cancer cells treated with anticancer agent TH287 or paclitaxel that causes M arrest, mitochondria accumulate robustly and produce excessive mitochondrial superoxide, which causes oxidative DNA damage and undermines cell survival and proliferation. While mitochondrial mass is greatly increased in cells arrested at M phase, the mitochondrial function is compromised, as reflected by reduced mitochondrial membrane potential, increased SUMOylation and acetylation of mitochondrial proteins, as well as an increased metabolic reliance on glycolysis. CHK1 functional disruption decelerates cell cycle, spares the M arrest and attenuates mitochondrial oxidative stress. Induction of mitophagy and blockade of mitochondrial biogenesis, measures that reduce mitochondrial accumulation, also decelerate cell cycle and abrogate M arrest-coupled mitochondrial oxidative stress. These results suggest that cell cycle progression and mitochondrial homeostasis are interdependent and coordinated, and that impairment of mitochondrial homeostasis and the associated redox signaling may mediate the antineoplastic effect of the M arrest-inducing chemotherapeutics. Our findings provide insights into the fate of cells arrested at M phase and have implications in cancer therapy.


Asunto(s)
Puntos de Control del Ciclo Celular/genética , Mitocondrias/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Homeostasis , Humanos , Mitosis , Estrés Oxidativo , Transducción de Señal
3.
Cancer Biol Med ; 18(1): 120-138, 2021 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-33628589

RESUMEN

Objective: RECQL4 (a member of the RECQ helicase family) upregulation has been reported to be associated with tumor progression in several malignancies. However, whether RECQL4 sustains esophageal squamous cell carcinoma (ESCC) has not been elucidated. In this study, we determined the functional role for RECQL4 in ESCC progression. Methods: RECQL4 expression in clinical samples of ESCC was examined by immunohistochemistry. Cell proliferation, cellular senescence, the epithelial-mesenchymal transition (EMT), DNA damage, and reactive oxygen species in ESCC cell lines with RECQL4 depletion or overexpression were analyzed. The levels of proteins involved in the DNA damage response (DDR), cell cycle progression, survival, and the EMT were determined by Western blot analyses. Results: RECQL4 was highly expressed in tumor tissues when compared to adjacent non-tumor tissues in ESCC (P < 0.001) and positively correlated with poor differentiation (P = 0.011), enhanced invasion (P = 0.033), and metastasis (P = 0.048). RECQL4 was positively associated with proliferation and migration in ESCC cells. Depletion of RECQL4 also inhibited growth of tumor xenografts in vivo. RECQL4 depletion induced G0/G1 phase arrest and cellular senescence. Importantly, the levels of DNA damage and reactive oxygen species were increased when RECQL4 was depleted. DDR, as measured by the activation of ATM, ATR, CHK1, and CHK2, was impaired. RECQL4 was also shown to promote the activation of AKT, ERK, and NF-kB in ESCC cells. Conclusions: The results indicated that RECQL4 was highly expressed in ESCC and played critical roles in the regulation of DDR, redox homeostasis, and cell survival.


Asunto(s)
Daño del ADN/genética , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas de Esófago/genética , RecQ Helicasas/genética , Animales , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Senescencia Celular/genética , Transición Epitelial-Mesenquimal , Neoplasias Esofágicas/enzimología , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/enzimología , Carcinoma de Células Escamosas de Esófago/patología , Regulación Neoplásica de la Expresión Génica , Homeostasis/genética , Humanos , Inmunohistoquímica , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Oxidación-Reducción , Especies Reactivas de Oxígeno/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
4.
Oxid Med Cell Longev ; 2021: 8189485, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34987705

RESUMEN

Solid tumors are usually associated with extracellular acidosis due to their increased dependence on glycolysis and poor vascularization. Cancer cells gradually become adapted to acidic microenvironment and even acquire increased aggressiveness. They are resistant to apoptosis but exhibit increased autophagy that is essential for their survival. We here show that NF-κB, a master regulator of cellular responses to stress, is upregulated in colorectal cancer cells adapted to acidosis (CRC-AA). NF-κB is more relied upon for survival in CRC-AA than in their parental cells and drives a robust antioxidant response. Supplementation of antioxidant abolishes the increased sensitivity of CRC-AA to NF-κB inhibition or depletion, suggesting that NF-κB supports the survival of CRC-AA by maintaining redox homeostasis. Because SQSTM1/p62 is known to mediate the selective autophagy of GATA4 that augments NF-κB function, we tested whether the enhanced autophagic flux and consequently the reduction of SQSTM1/p62 in CRC-AA cells could activate the GATA4-NF-κB axis. Indeed, GATA4 is upregulated in CRC-AA cells and augments the NF-κB activity that underlies the increased expression of cytokines, inhibition of apoptosis, and reduction of reactive oxygen species. Interestingly, secretory factors derived from HCT15-AA cells, the soluble ICAM-1 in particular, also possess antioxidant cytoprotective effect against acidic stress. Together, our results demonstrate a prosurvival role of the p62-restricted GATA4-NF-κB axis in cancer cells adapted to acidic microenvironment.


Asunto(s)
Acidosis/tratamiento farmacológico , Antioxidantes/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Factor de Transcripción GATA4/metabolismo , FN-kappa B/metabolismo , Animales , Antioxidantes/farmacología , Autofagia , Enfermedad Crónica , Neoplasias Colorrectales/mortalidad , Humanos , Ratones , Análisis de Supervivencia , Microambiente Tumoral
5.
Oxid Med Cell Longev ; 2020: 2015920, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32908624

RESUMEN

Autophagy has been well documented to play an important role in maintaining genomic stability. However, in addition to directly engulfing and digesting the damaged organelles and chromatin fragments, autophagy can affect many cellular processes including DNA damage response, regulation of redox homeostasis, and cell division; it remains to be determined to what extent each of those processes contributes to the maintenance of genomic stability. We here examined the role of autophagy-dependent redox regulation in the maintenance of genomic stability in two cancer cell lines (HT1080 and U2OS) and mesenchymal stem cells (MSCs) using micronuclei MN, also referred to as cytoplasmic chromatin fragments, as a marker. Our results showed that the spontaneous and genotoxic stress-induced frequencies of MN in cancer cells were significantly reduced by autophagy activators rapamycin and Torin1, and the reduction in MN was accompanied by a reduction in reactive oxygen species (ROS). Increased micronucleation in senescent MSCs, in which autophagic flux is blocked, was also attenuated by rapamycin, together with a reduction in ROS. Inhibition of autophagy by chloroquine (CQ) or ATG5 depletion, on the other hand, resulted in an increased frequency of MN, though a ROS elevation in response to autophagy inhibition was only observed in MSCs. Importantly, the induction of MN by autophagy inhibition in MSCs could be abrogated by antioxidant N-acetylcysteine (NAC). In contrast to the reported impairment of CHK1 activation in Atg7-deficient mouse embryonic fibroblasts, we found that the level of phosphorylated CHK1 was increased by CQ or ATG5 depletion but decreased by rapamycin or Torin1, suggesting that the increased genomic instability by defective autophagy is not caused by insufficient activation of CHK1-homologous recombination cascade. Together, our findings suggest that redox homeostasis regulated by autophagy contributes substantially to the maintenance of genomic stability in certain contexts.


Asunto(s)
Autofagia/genética , Inestabilidad Genómica , Estrés Oxidativo/genética , Antioxidantes/farmacología , Autofagia/efectos de los fármacos , Línea Celular Tumoral , Senescencia Celular/efectos de los fármacos , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/metabolismo , Inestabilidad Genómica/efectos de los fármacos , Humanos , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/metabolismo , Micronúcleos con Defecto Cromosómico , Mutágenos/toxicidad , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Sirolimus/farmacología
6.
Redox Biol ; 36: 101604, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32554304

RESUMEN

Ovarian cancer is the most lethal gynecological malignancy. Abnormal homologous recombination repair, high level of reactive oxygen species (ROS) and upregulation of antioxidant genes are characteristic features of ovarian cancer. However, the molecular mechanisms governing the redox homeostasis in ovarian cancer cells remain to be fully elucidated. We here demonstrated a critical role of RAD51, a protein essential for homologous recombination, in the maintenance of redox homeostasis. We found that RAD51 is overexpressed in high grade serous ovarian cancer and is associated with poor prognosis. Depletion or inhibition of RAD51 results in G2/M arrest, increased production of reactive oxygen species and accumulation of oxidative DNA damage. Importantly, antioxidant N-acetylcysteine (NAC) significantly attenuated the induction of DNA damage and the perturbation of proliferation caused by RAD51 depletion. We further demonstrated that RAD51 inhibition or depletion led to elevated production of mitochondrial superoxide and increased accumulation of mitochondria. Moreover, CHK1 activation is required for the G2/M arrest and the generation of mitochondrial stress in response to RAD51 depletion. Together, our results indicate that nuclear DNA damage caused by RAD51 depletion may trigger mitochondria-originated redox dysregulation. Our findings suggest that a vicious cycle of nuclear DNA damage, mitochondrial accumulation and oxidative stress may contribute to the tumor-suppressive effects of RAD51 depletion or inhibition.


Asunto(s)
Neoplasias Ováricas , Superóxidos , Apoptosis , Línea Celular Tumoral , Daño del ADN , Femenino , Puntos de Control de la Fase G2 del Ciclo Celular , Humanos , Mitocondrias/genética , Mitocondrias/metabolismo , Neoplasias Ováricas/genética , Estrés Oxidativo , Recombinasa Rad51/genética , Recombinasa Rad51/metabolismo , Especies Reactivas de Oxígeno
7.
Cell Death Dis ; 8(10): e3070, 2017 10 05.
Artículo en Inglés | MEDLINE | ID: mdl-28981112

RESUMEN

Many cancer drugs exert their therapeutic effect by inducing oxidative stress in the cancer cells. Oxidative stress compromises cell survival by inflicting lesions in macromolecules like DNA. Cancer cells rely on enhanced antioxidant metabolism and increased DNA repair function to survive oxidative assault. PARP1, a protein that senses DNA-strand breaks and orchestrates their repair, has an important role in the repair of oxidative DNA damage. Berberine, an alkaloid compound present in many herbal plants, is capable of inducing oxidative DNA damage and downregulating homologous recombination repair (HRR) in cancer cells. In this study, we demonstrated that berberine and PARP inhibitor niraparib have a synthetic lethal effect on ovarian cancer cells. Oxidative DNA damage was greatly induced by berberine in ovarian cancer cells. In addition, the level of RAD51 and the capacity of HRR were also reduced by berberine. Correspondingly, PARP became hyperactivated in response to berberine treatment. Cancer cells treated with berberine and niraparib in combination exhibited greatly increased apoptosis and remarkably reduced tumor growth in vivo. Together, the results indicate that by inducing oxidative DNA damage and downregulating HRR in cancer cells berberine is able to further sensitize cancer cells to PARP inhibition. Our findings demonstrate a potential therapeutic value of combined application of berberine and PARP inhibitors in ovarian cancer treatment.


Asunto(s)
Berberina/administración & dosificación , Neoplasias Ováricas/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , Inhibidores de Poli(ADP-Ribosa) Polimerasas/administración & dosificación , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Daño del ADN/efectos de los fármacos , Femenino , Humanos , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Poli(ADP-Ribosa) Polimerasas/genética , Recombinasa Rad51/genética , Reparación del ADN por Recombinación/efectos de los fármacos
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA
...