ABSTRACT
Disruption of the reprogrammed energy management system of malignant cells is a prioritized goal of targeted cancer therapy. Two regulators of this system are the Fer kinase, and its cancer cell specific variant, FerT, both residing in subcellular compartments including the mitochondrial electron transport chain. Here, we show that a newly developed inhibitor of Fer and FerT, E260, selectively evokes metabolic stress in cancer cells by imposing mitochondrial dysfunction and deformation, and onset of energy-consuming autophagy which decreases the cellular ATP level. Notably, Fer was also found to associate with PARP-1 and E260 disrupted this association thereby leading to PARP-1 activation. The cooperative intervention with these metabolic pathways leads to energy crisis and necrotic death in malignant, but not in normal human cells, and to the suppression of tumors growth in vivo. Thus, E260 is a new anti-cancer agent which imposes metabolic stress and cellular death in cancer cells.The tyrosine-kinases Fer/FerT associate with the mitochondrial electron transport chain in cancer cells supporting their metabolic reprogramming. Here the authors discover a compound that disrupts Fer /FerT activity and selectively induces cell death of cancer cell lines displaying anti-tumor activity in vivo.
Subject(s)
Colonic Neoplasms/drug therapy , Protein Kinase Inhibitors/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Stress, Physiological/drug effects , Xenograft Model Antitumor Assays , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Cell Line , Cell Line, Tumor , Cell Survival/drug effects , Colonic Neoplasms/genetics , Colonic Neoplasms/metabolism , HCT116 Cells , HT29 Cells , Humans , Mice, Inbred ICR , Mitochondria/drug effects , Mitochondria/metabolism , Necrosis , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Protein-Tyrosine Kinases/metabolism , Tumor Burden/drug effectsABSTRACT
Space applications have evolved to play a significant role in disaster relief by providing services including remote sensing imagery for mitigation and disaster damage assessments; satellite communication to provide access to medical services; positioning, navigation, and timing services; and data sharing. Common issues identified in past disaster response and relief efforts include lack of communication, delayed ordering of actions (eg, evacuations), and low levels of preparedness by authorities during and after disasters. We briefly summarize the Space for Health (S4H) Team Project, which was prepared during the Space Studies Program 2014 within the International Space University. The S4H Project aimed to improve the way space assets and experiences are used in support of public health during disaster relief efforts. We recommend an integrated solution based on nano-satellites or a balloon communication system, mobile self-contained relief units, portable medical scanning devices, and micro-unmanned vehicles that could revolutionize disaster relief and disrupt different markets. The recommended new system of coordination and communication using space assets to support public health during disaster relief efforts is feasible. Nevertheless, further actions should be taken by governments and organizations in collaboration with the private sector to design, test, and implement this system.
Subject(s)
Disaster Planning/methods , Public Health Practice , Satellite Communications , Humans , Information Dissemination , Satellite Communications/economicsABSTRACT
The kinase Fer and its spermatogenic meiotic variant, FerT, are coexpressed in normal testes and cancerous tumors, but whether they exert related roles in spermatogenic or malignant cells has not been known. Here, we show that Fer and FerT reside in the mitochondria of spermatogenic cells and are harnessed to the reprogrammed mitochondria of colon carcinoma cells. Both kinases bound complex I of the mitochondrial electron transport chain (ETC) in spermatogenic and in colon carcinoma cells, and silencing of either Fer or FerT was sufficient to impair the activity of this complex. Directed mitochondrial accumulation of FerT in nonmalignant NIH3T3 cells increased their ETC complex I activity, ATP production, and survival, contingent upon stress conditions caused by nutrient and oxygen deprivation. Strikingly, directed mitochondrial accumulation of FerT endowed nonmalignant cells with tumor-forming ability. Thus, recruitment of a meiotic mitochondrial component to cancer cell mitochondria highlights a pivotal role for reprogrammed mitochondria in tumorigenesis.
Subject(s)
Colonic Neoplasms/etiology , Protein-Tyrosine Kinases/physiology , Adenosine Triphosphate/biosynthesis , Animals , Cells, Cultured , Electron Transport Complex I/physiology , Female , Humans , Male , Mice , Mice, Inbred ICR , Mitochondria/metabolism , NIH 3T3 CellsABSTRACT
Fer is an intracellular tyrosine kinase which resides in both the cytoplasm and nucleus of mammalian cells. This kinase was also found in all malignant cell-lines analyzed and was shown to support cell-cycle progression in cancer cells. Herein we show that knock-down of Fer, both, impairs cell-cycle progression and imposes programmed cell death in colon carcinoma (CC) cells. The cell-cycle arrest and apoptotic death invoked by the depletion of Fer were found to depend on the activity of p53. Accordingly, down regulation of Fer led to the activation of the Ataxia Telangiectasia Mutated protein (ATM) and its down-stream effector-p53. Knock-down of Fer also increased the level of Reactive-Oxygen Species (ROS) in CC cells, and subjection of Fer depleted cells to ROS neutralizing scavengers significantly decreased the induced phosphorylation and activation of ATM and p53. Notably, over-expression of Fer opposed the Doxorubicin driven activation of ATM and p53, which can be mediated by ROS. Collectively, our findings imply that Fer sustains low ROS levels in CC cells, thereby restraining the activation of ATM and p53 in these cells.
Subject(s)
Apoptosis , Cell Cycle Proteins/metabolism , Colonic Neoplasms/metabolism , DNA-Binding Proteins/metabolism , Protein Serine-Threonine Kinases/metabolism , Protein-Tyrosine Kinases/metabolism , Tumor Suppressor Protein p53/metabolism , Tumor Suppressor Proteins/metabolism , Ataxia Telangiectasia Mutated Proteins , Cell Cycle , Cell Cycle Proteins/genetics , Cell Line, Tumor , Colonic Neoplasms/genetics , DNA-Binding Proteins/genetics , Gene Expression Regulation, Neoplastic , HCT116 Cells , Humans , Mutation , Phosphorylation , Protein Serine-Threonine Kinases/genetics , Protein-Tyrosine Kinases/genetics , RNA, Small Interfering/genetics , Reactive Oxygen Species/metabolism , Signal Transduction , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Proteins/geneticsABSTRACT
Fer is an intracellular tyrosine kinase that accumulates in most mammalian tissues. A truncated variant of Fer, FerT, is uniquely detected in spermatogenic cells and is absent from normal somatic tissues. Here, we show that in addition to Fer, FerT also accumulates in CC cells and in metastases derived from colorectal tumors, but not in normal human cells. Thus, FerT is a new member of the CTA protein family. Transcription of the ferT gene in CC cells was found to be driven by an intronic promoter residing in intron 10 of the fer gene and to be regulated by another CTA, the Brother of the Regulator of Imprinted Sites (BORIS) transcription factor. BORIS binds to the ferT promoter and down-regulation of BORIS significantly decreases the expression of ferT in CC cells. Accumulation of the ferT RNA was also regulated by the DNA methylation status and paralleled the expression profile of the boris transcript. Accordingly, the intronic ferT promoter was found to be hypomethylated in cancer cells expressing the FerT protein, by comparison with non-expressers. Collectively, we show here that FerT is a new CTA whose accumulation in CC cells, commonly considered low CTA expressers, is controlled by a novel transcription regulatory mechanism.
