RESUMO
Melatonin is one of the most phylogenetically conserved signals in biology. Although its original function was probably related to its antioxidant capacity, this indoleamine has been "adopted" by multicellular organisms as the "darkness signal" when secreted in a circadian manner and is acutely suppressed by light at night by the pineal gland. However, melatonin is also produced by other tissues, which constitute its extrapineal sources. Apart from its undisputed chronobiotic function, melatonin exerts antioxidant, immunomodulatory, pro-apoptotic, antiproliferative, and anti-angiogenic effects, with all these properties making it a powerful antitumor agent. Indeed, this activity has been demonstrated to be mediated by interfering with various cancer hallmarks, and different epidemiological studies have also linked light at night (melatonin suppression) with a higher incidence of different types of cancer. In 2007, the World Health Organization classified night shift work as a probable carcinogen due to circadian disruption, where melatonin plays a central role. Our aim is to review, from a global perspective, the role of melatonin both from pineal and extrapineal origin, as well as their possible interplay, as an intrinsic factor in the incidence, development, and progression of cancer. Particular emphasis will be placed not only on those mechanisms related to melatonin's antioxidant nature but also on the recently described novel roles of melatonin in microbiota and epigenetic regulation.
RESUMO
Chromatin is a barrier to efficient DNA repair, as it hinders access and processing of certain DNA lesions. ALC1/CHD1L is a nucleosome-remodeling enzyme that responds to DNA damage, but its precise function in DNA repair remains unknown. Here we report that loss of ALC1 confers sensitivity to PARP inhibitors, methyl-methanesulfonate, and uracil misincorporation, which reflects the need to remodel nucleosomes following base excision by DNA glycosylases but prior to handover to APEX1. Using CRISPR screens, we establish that ALC1 loss is synthetic lethal with homologous recombination deficiency (HRD), which we attribute to chromosome instability caused by unrepaired DNA gaps at replication forks. In the absence of ALC1 or APEX1, incomplete processing of BER intermediates results in post-replicative DNA gaps and a critical dependence on HR for repair. Hence, targeting ALC1 alone or as a PARP inhibitor sensitizer could be employed to augment existing therapeutic strategies for HRD cancers.
Assuntos
Montagem e Desmontagem da Cromatina , DNA Helicases/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias Experimentais/metabolismo , Nucleossomos/metabolismo , Poli(ADP-Ribose) Polimerases/metabolismo , Animais , DNA Helicases/genética , Replicação do DNA/efeitos dos fármacos , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/genética , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/metabolismo , Proteínas de Ligação a DNA/genética , Recombinação Homóloga/efeitos dos fármacos , Camundongos , Camundongos Knockout , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Neoplasias Experimentais/genética , Nucleossomos/genética , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Poli(ADP-Ribose) Polimerases/genéticaRESUMO
The cell cycle is a tightly regulated process that is controlled by the conserved cyclin-dependent kinase (CDK)-cyclin protein complex1. However, control of the G0-to-G1 transition is not completely understood. Here we demonstrate that p38 MAPK gamma (p38γ) acts as a CDK-like kinase and thus cooperates with CDKs, regulating entry into the cell cycle. p38γ shares high sequence homology, inhibition sensitivity and substrate specificity with CDK family members. In mouse hepatocytes, p38γ induces proliferation after partial hepatectomy by promoting the phosphorylation of retinoblastoma tumour suppressor protein at known CDK target residues. Lack of p38γ or treatment with the p38γ inhibitor pirfenidone protects against the chemically induced formation of liver tumours. Furthermore, biopsies of human hepatocellular carcinoma show high expression of p38γ, suggesting that p38γ could be a therapeutic target in the treatment of this disease.
Assuntos
Carcinogênese/patologia , Ciclo Celular , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/patologia , Fígado/enzimologia , Fígado/patologia , Proteína Quinase 12 Ativada por Mitógeno/metabolismo , Idoso , Animais , Carcinogênese/efeitos dos fármacos , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/patologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Quinases Ciclina-Dependentes/antagonistas & inibidores , Quinases Ciclina-Dependentes/metabolismo , Feminino , Hepatócitos/citologia , Hepatócitos/patologia , Humanos , Fígado/cirurgia , Neoplasias Hepáticas/induzido quimicamente , Masculino , Camundongos , Pessoa de Meia-Idade , Proteína Quinase 12 Ativada por Mitógeno/antagonistas & inibidores , Fosforilação , Piridonas/farmacologia , Proteína do Retinoblastoma/química , Proteína do Retinoblastoma/metabolismo , Homologia de Sequência , Especificidade por SubstratoRESUMO
Hepatocellular carcinoma (HCC) is the sixth most common cancer type and the fourth leading cause of cancer-related death. This cancer appears with higher incidence in men and during obesity; however, the specific mechanisms underlying this correlation are unknown. Adipose tissue, a key organ in metabolic syndrome, shows evident gender disparities in the production of adipokines. Levels of the important adipokine adiponectin decrease in men during puberty, as well as in the obese state. Here, we show that this decrease in adiponectin levels is responsible for the increased liver cancer risk in males. We found that testosterone activates the protein JNK in mouse and human adipocytes. JNK-mediated inhibition of adiponectin secretion increases liver cancer cell proliferation, since adiponectin protects against liver cancer development through the activation of AMP-activated protein kinase (AMPK) and p38α. This study provides insight into adipose tissue to liver crosstalk and its gender relation during cancer development, having the potential to guide strategies for new cancer therapeutics.
Assuntos
Adiponectina/sangue , Carcinoma Hepatocelular/epidemiologia , Cálculos Biliares/sangue , Neoplasias Hepáticas/epidemiologia , Proteínas Quinases Ativadas por AMP/metabolismo , Adipócitos/metabolismo , Adiponectina/genética , Tecido Adiposo/metabolismo , Animais , Estudos de Coortes , Feminino , Cálculos Biliares/cirurgia , Humanos , Incidência , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Obesidade/metabolismo , Fatores SexuaisRESUMO
Activation of poly(ADP-ribose) polymerase (PARP) near sites of DNA breaks facilitates recruitment of DNA repair proteins and promotes chromatin relaxation in part through the action of chromatin-remodeling enzyme Amplified in Liver Cancer 1 (ALC1). Through proteomic analysis we find that ALC1 interacts after DNA damage with Tripartite Motif-containing 33 (TRIM33), a multifunctional protein implicated in transcriptional regulation, TGF-ß signaling, and tumorigenesis. We demonstrate that TRIM33 is dynamically recruited to DNA damage sites in a PARP1- and ALC1-dependent manner. TRIM33-deficient cells show enhanced sensitivity to DNA damage and prolonged retention of ALC1 at sites of DNA breaks. Conversely, overexpression of TRIM33 alleviates the DNA repair defects conferred by ALC1 overexpression. Thus, TRIM33 plays a role in PARP-dependent DNA damage response and regulates ALC1 activity by promoting its timely removal from sites of DNA damage.
Assuntos
Quebras de DNA , DNA Helicases/metabolismo , Reparo do DNA/fisiologia , Proteínas de Ligação a DNA/metabolismo , Poli(ADP-Ribose) Polimerases/metabolismo , Fatores de Transcrição/metabolismo , Animais , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Células HEK293 , Humanos , Camundongos , Camundongos Knockout , Poli(ADP-Ribose) Polimerase-1 , Poli(ADP-Ribose) Polimerases/genética , Proteômica , Fatores de Transcrição/genética , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismoRESUMO
The appropriate execution of DNA double-strand break (DSB) repair is critical for genome stability and tumor avoidance. 53BP1 and BRCA1 directly influence DSB repair pathway choice by regulating 5' end resection, but how this is achieved remains uncertain. Here we report that Rif1(-/-) mice are severely compromised for 53BP1-dependent class switch recombination (CSR) and fusion of dysfunctional telomeres. The inappropriate accumulation of RIF1 at DSBs in S phase is antagonized by BRCA1, and deletion of Rif1 suppresses toxic nonhomologous end joining (NHEJ) induced by PARP inhibition in Brca1-deficient cells. Mechanistically, RIF1 is recruited to DSBs via the N-terminal phospho-SQ/TQ domain of 53BP1, and DSBs generated by ionizing radiation or during CSR are hyperresected in the absence of RIF1. Thus, RIF1 and 53BP1 cooperate to block DSB resection to promote NHEJ in G1, which is antagonized by BRCA1 in S phase to ensure a switch of DSB repair mode to homologous recombination.
Assuntos
Proteínas Cromossômicas não Histona/genética , Quebras de DNA de Cadeia Dupla , Reparo do DNA por Junção de Extremidades , Proteínas de Ligação a DNA/genética , DNA/metabolismo , Proteínas de Ligação a Telômeros/genética , Animais , Proteínas Cromossômicas não Histona/metabolismo , Proteínas de Ligação a DNA/metabolismo , Células HeLa , Humanos , Camundongos , Recombinação Genética , Telômero/metabolismo , Proteínas de Ligação a Telômeros/metabolismo , Transfecção , Proteína 1 de Ligação à Proteína Supressora de Tumor p53RESUMO
Telomerase confers limitless proliferative potential to most human cells through its ability to elongate telomeres, the natural ends of chromosomes, which otherwise would undergo progressive attrition and eventually compromise cell viability. However, the role of telomerase in organismal aging has remained unaddressed, in part because of the cancer-promoting activity of telomerase. To circumvent this problem, we have constitutively expressed telomerase reverse transcriptase (TERT), one of the components of telomerase, in mice engineered to be cancer resistant by means of enhanced expression of the tumor suppressors p53, p16, and p19ARF. In this context, TERT overexpression improves the fitness of epithelial barriers, particularly the skin and the intestine, and produces a systemic delay in aging accompanied by extension of the median life span. These results demonstrate that constitutive expression of Tert provides antiaging activity in the context of a mammalian organism.
Assuntos
Envelhecimento , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Neoplasias/genética , Neoplasias/metabolismo , Telomerase/metabolismo , Animais , Sobrevivência Celular , Epiderme/metabolismo , Humanos , Fator de Crescimento Insulin-Like I/biossíntese , Queratinócitos/citologia , Camundongos , Camundongos Transgênicos , Modelos Biológicos , Células-Tronco/citologiaRESUMO
There is a great interest in determining the impact of p53 on ageing and, for this, it is important to discriminate among the known causes of ageing. Telomere loss is a well-established source of age-associated damage, which by itself can recapitulate ageing in mouse models. Here, we have used a genetic approach to interrogate whether p53 contributes to the elimination of telomere-damaged cells and its impact on telomere-driven ageing. We have generated compound mice carrying three functional copies of the p53 gene (super-p53) in a telomerase-deficient background and we have measured the presence of chromosomal abnormalities and DNA damage in several tissues. We have found that the in vivo load of telomere-derived chromosomal damage is significantly decreased in super-p53/telomerase-null mice compared with normal-p53/telomerase-null mice. Interestingly, the presence of extra p53 activity neither accelerates nor delays telomere-driven ageing. From these observations, we conclude that p53 has an active role in eliminating telomere-damaged cells, and we exclude the possibility of an age-promoting effect of p53 on telomere-driven ageing.