ABSTRACT
Adapting to changes in nutrient availability and environmental conditions is a fundamental property of cells. This adaptation requires a multi-directional coordination between metabolism, growth, and the cell cycle regulators (consisting of the family of cyclin-dependent kinases (CDKs), their regulatory subunits known as cyclins, CDK inhibitors, the retinoblastoma family members, and the E2F transcription factors). Deciphering the mechanisms accountable for this coordination is crucial for understanding various patho-physiological processes. While it is well established that metabolism and growth affect cell division, this review will focus on recent observations that demonstrate how cell cycle regulators coordinate metabolism, cell cycle progression, and growth. We will discuss how the cell cycle regulators directly regulate metabolic enzymes and pathways and summarize their involvement in the endolysosomal pathway and in the functions and dynamics of mitochondria.
Subject(s)
Cell Cycle/genetics , Cyclin-Dependent Kinase Inhibitor Proteins/genetics , Cyclin-Dependent Kinases/genetics , Cyclins/genetics , Nutritive Value/physiology , Adaptation, Physiological , Animals , Cell Cycle/drug effects , Cells, Cultured , Cyclin-Dependent Kinase Inhibitor Proteins/metabolism , Cyclin-Dependent Kinases/antagonists & inhibitors , Cyclin-Dependent Kinases/metabolism , Cyclins/metabolism , E2F Transcription Factors/genetics , E2F Transcription Factors/metabolism , Endosomes/drug effects , Endosomes/metabolism , Gene Expression Regulation , Humans , Lysosomes/drug effects , Lysosomes/metabolism , Mitochondria/drug effects , Mitochondria/metabolism , Protein Kinase Inhibitors/pharmacology , Retinoblastoma Protein/genetics , Retinoblastoma Protein/metabolism , Saccharomyces cerevisiae/drug effects , Saccharomyces cerevisiae/growth & development , Saccharomyces cerevisiae/metabolism , Signal TransductionABSTRACT
This study investigated the role of CDK4 in the oxidative metabolism of brown adipose tissue (BAT). BAT from Cdk4-/- mice exhibited fewer lipids and increased mitochondrial volume and expression of canonical thermogenic genes, rendering these mice more resistant to cold exposure. Interestingly, these effects were not BAT cell-autonomous but rather driven by increased sympathetic innervation. In particular, the ventromedial hypothalamus (VMH) is known to modulate BAT activation via the sympathetic nervous system. We thus examined the effects of VMH neuron-specific Cdk4 deletion. These mice display increased sympathetic innervation and enhanced cold tolerance, similar to Cdk4-/- mice, in addition to browning of scWAT. Overall, we provide evidence showing that CDK4 modulates thermogenesis by regulating sympathetic innervation of adipose tissue depots through hypothalamic nuclei, including the VMH. This demonstrates that CDK4 not only negatively regulates oxidative pathways, but also modulates the central regulation of metabolism through its action in the brain.
Subject(s)
Adipose Tissue, White , Thermogenesis , Adipocytes, Brown , Adipose Tissue, Brown , Animals , Hypothalamus , Mice , Thermogenesis/geneticsABSTRACT
Cancer proliferation and progression involves altered metabolic pathways as a result of continuous demand for energy and nutrients. In the last years, cell cycle regulators have been involved in the control of metabolic processes, such as glucose and insulin pathways and lipid synthesis, in addition to their canonical function controlling cell cycle progression. Here we describe recent data demonstrating the role of cell cycle regulators in the metabolic control especially in studies performed in cancer models. Moreover, we discuss the importance of these findings in the context of current cancer therapies to provide an overview of the relevance of targeting metabolism using inhibitors of the cell cycle regulation.
Subject(s)
Cyclin-Dependent Kinase Inhibitor Proteins/metabolism , Cyclin-Dependent Kinases/metabolism , Cyclins/metabolism , Neoplasms/pathology , Protein Kinase Inhibitors/therapeutic use , Animals , Carcinogenesis/drug effects , Carcinogenesis/genetics , Carcinogenesis/pathology , Cell Cycle/drug effects , Cell Cycle/genetics , Cell Line, Tumor , Cyclin-Dependent Kinase Inhibitor Proteins/genetics , Cyclin-Dependent Kinases/antagonists & inhibitors , Cyclin-Dependent Kinases/genetics , Cyclins/genetics , Disease Models, Animal , Disease Progression , Energy Metabolism/drug effects , Energy Metabolism/physiology , Gene Expression Regulation, Neoplastic/drug effects , Humans , Mitochondria/drug effects , Mitochondria/metabolism , Mutation , Neoplasms/drug therapy , Neoplasms/genetics , Protein Kinase Inhibitors/pharmacologyABSTRACT
Cyclin-dependent kinase 4 (CDK4) is well-known for its role in regulating the cell cycle, however, its role in cancer metabolism, especially mTOR signaling, is undefined. In this study, we established a connection between CDK4 and lysosomes, an emerging metabolic organelle crucial for mTORC1 activation. On the one hand, CDK4 phosphorylated the tumor suppressor folliculin (FLCN), regulating mTORC1 recruitment to the lysosomal surface in response to amino acids. On the other hand, CDK4 directly regulated lysosomal function and was essential for lysosomal degradation, ultimately regulating mTORC1 activity. Pharmacologic inhibition or genetic inactivation of CDK4, other than retaining FLCN at the lysosomal surface, led to the accumulation of undigested material inside lysosomes, which impaired the autophagic flux and induced cancer cell senescence in vitro and in xenograft models. Importantly, the use of CDK4 inhibitors in therapy is known to cause senescence but not cell death. To overcome this phenomenon and based on our findings, we increased the autophagic flux in cancer cells by using an AMPK activator in combination with a CDK4 inhibitor. The cotreatment induced autophagy (AMPK activation) and impaired lysosomal function (CDK4 inhibition), resulting in cell death and tumor regression. Altogether, we uncovered a previously unknown role for CDK4 in lysosomal biology and propose a novel therapeutic strategy to target cancer cells. SIGNIFICANCE: These findings uncover a novel function of CDK4 in lysosomal biology, which promotes cancer progression by activating mTORC1; targeting this function offers a new therapeutic strategy for cancer treatment.
Subject(s)
Cyclin-Dependent Kinase 4/physiology , Lysosomes/physiology , Mechanistic Target of Rapamycin Complex 1/metabolism , Neoplasm Proteins/physiology , Adenylate Kinase/metabolism , Aminopyridines/pharmacology , Aminopyridines/therapeutic use , Animals , Autophagosomes/physiology , Autophagy/physiology , Benzimidazoles/pharmacology , Benzimidazoles/therapeutic use , Biphenyl Compounds , Cell Line, Tumor , Cellular Senescence/physiology , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Cyclin-Dependent Kinase 4/genetics , Drug Synergism , Female , Gene Knockout Techniques , Humans , Insulin/physiology , Lysosomes/ultrastructure , Mice , Mice, Inbred NOD , Molecular Targeted Therapy , Phosphorylation , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Protein Processing, Post-Translational , Protein Transport , Proto-Oncogene Proteins/metabolism , Pyrones/pharmacology , Pyrones/therapeutic use , Recombinant Fusion Proteins/metabolism , Signal Transduction/physiology , Thiophenes/pharmacology , Thiophenes/therapeutic use , Tumor Suppressor Proteins/metabolism , Xenograft Model Antitumor AssaysABSTRACT
INTRODUCTION: The information about defects affecting natural killer cell (NK) development and activity in patients with an abnormal increase of recurrent infections is scarce. OBJECTIVE: To perform a systematic analysis of NK abnormalities in patients with recurrent infections. MATERIALS AND METHODS: Our study enrolled twenty patients with severe or recurrent viral infections. Natural killer cell subsets, surface receptors expression and cytotoxicity were analyzed. Results were compared with those from age- and sex-matched healthy controls. RESULTS: Transient alterations were observed in the percentages and absolute numbers of NK cells in patients with infection active episodes. We also described five patients with stable disturbances in the distribution of NK cell subpopulations. These defects are mainly due to a decrease in the CD56 dim CD16 bright cells in peripheral blood. In addition, NK cell function abnormalities were observed in some patients, however, those were always transient and mainly associated to active disease. CONCLUSIONS: These findings demonstrate transient alterations in the percentages and absolute numbers of NK cells in patients with recurrent or severe infection. Also, stable disturbances in CD56 dim CD16 bright NK cells are observed in these patients. Nevertheless, these parameters must be thoroughly studied to determine the mechanisms that entail these immune abnormalities and investigate how they alter the immune response.
Subject(s)
Killer Cells, Natural/physiology , Virus Diseases/immunology , Adolescent , Adult , Aged , Child , Child, Preschool , Female , Humans , Lymphocyte Count , Male , Middle Aged , Recurrence , Severity of Illness Index , Young AdultABSTRACT
Introducción. Existen pocos datos sobre los defectos que afectan el desarrollo y función de los linfocitos asesinos naturales ( natural killers, NK) en pacientes con un incremento anormal en la recurrencia de infecciones. Objetivo. Realizar una evaluación sistemática de las diferentes subpoblaciones y la función de estas células en pacientes con infecciones recurrentes. Materiales y métodos. Se incluyeron 20 pacientes con infecciones graves o recurrentes y se analizaron las subpoblaciones y la respuesta citotóxica de los linfocitos NK en sangre periférica. Los resultados de los pacientes se compararon con controles sanos pareados por edad y sexo. Resultados. Los pacientes con episodios infecciosos activos presentaron anormalidades transitorias en el porcentaje o el número absoluto de linfocitos NK. Se caracterizaron, además, cinco pacientes con alteraciones persistentes en la distribución de las subpoblaciones de linfocitos NK. Estas alteraciones se debieron principalmente a la disminución de células CD56 dim CD16 bright . Se evidenciaron, también, defectos en la función de los linfocitos NK en algunos de nuestros pacientes; sin embargo, estas alteraciones fueron transitorias y se asociaron principalmente a la fase activa de la enfermedad. Conclusiones. Nuestros resultados evidencian defectos transitorios en el número y función de los linfocitos NK en pacientes con infecciones recurrentes o graves, además de alteraciones persistentes en los LNK CD56 dim CD16 bright en algunos individuos. Es necesario profundizar en los mecanismos que conllevan al desarrollo de estos defectos inmunes y estudiar cómo estas alteraciones influyen en la respuesta inmune.
Introduction: The information about defects affecting natural killer cell (NK) development and activity in patients with an abnormal increase of recurrent infections is scarce. Objective: To perform a systematic analysis of NK abnormalities in patients with recurrent infections. Materials and methods: Our study enrolled twenty patients with severe or recurrent viral infections. Natural killer cell subsets, surface receptors expression and cytotoxicity were analyzed. Results were compared with those from age- and sex-matched healthy controls. Results: Transient alterations were observed in the percentages and absolute numbers of NK cells in patients with infection active episodes. We also described five patients with stable disturbances in the distribution of NK cell subpopulations. These defects are mainly due to a decrease in the CD56 dim CD16 bright cells in peripheral blood. In addition, NK cell function abnormalities were observed in some patients, however, those were always transient and mainly associated to active disease. Conclusions: These findings demonstrate transient alterations in the percentages and absolute numbers of NK cells in patients with recurrent or severe infection. Also, stable disturbances in CD56 dim CD16 bright NK cells are observed in these patients. Nevertheless, these parameters must be thoroughly studied to determine the mechanisms that entail these immune abnormalities and investigate how they alter the immune response.
Subject(s)
Adolescent , Adult , Aged , Child , Child, Preschool , Female , Humans , Male , Middle Aged , Young Adult , Killer Cells, Natural/physiology , Virus Diseases/immunology , Lymphocyte Count , Recurrence , Severity of Illness IndexABSTRACT
Familial hemophagocytic lymphohistiocytosis (FHL), is a rare autosomal recessive disorder characterized by an impairment of cytotoxic cells and uncontrolled activation of macrophages. This study presents the first description of four patients with FHL type 2 in Latin America. Patient 1 fulfilled the disease diagnostic criteria since 2 months of age, whereas patients 2, 3 and 4 exhibited the typical manifestations of the disease only later in their childhood. The PRF1 genetic analysis in these patients revealed two previously reported mutations: L17fsx50 and R54C. Interestingly, seven out of the 8 alleles evaluated here in patients carried the haplotype R54C/A91V, suggesting that this is a highly frequent FHL type 2 allele in Colombia. This haplotype confers residual cytotoxic function leading to late onset disease. Therefore, this report highlights the remarkable complexity of FHL diagnostic, emphasizing the importance of the genetic characterization of the disease.
