A5022922854- Cancer, Hypoxia, and Metabolism
- Metabolism, Diabetes, and Cancer
- Epigenetics and DNA Methylation
- RNA modifications and cancer
- Adipose Tissue and Metabolism
- Histone Deacetylase Inhibitors Research
- Pancreatic function and diabetes
- Polyamine Metabolism and Applications
- Mitochondrial Function and Pathology
- Autophagy in Disease and Therapy
- Cancer-related Molecular Pathways
- Metabolism and Genetic Disorders
- Amino Acid Enzymes and Metabolism
- CRISPR and Genetic Engineering
- RNA Research and Splicing
- Genetics, Aging, and Longevity in Model Organisms
- PI3K/AKT/mTOR signaling in cancer
- Melanoma and MAPK Pathways
- Multiple Myeloma Research and Treatments
- Cell Adhesion Molecules Research
- Acute Myeloid Leukemia Research
- RNA and protein synthesis mechanisms
- Cancer-related gene regulation
- Heat shock proteins research
- Tuberous Sclerosis Complex Research
McGill University
2014-2025
Jewish General Hospital
2019-2025
McGill University Health Centre
2016-2017
<ns4:p>The mammalian/mechanistic target of rapamycin (mTOR) is a key component cellular metabolism that integrates nutrient sensing with processes fuel cell growth and proliferation. Although the involvement mTOR pathway in regulating life span aging has been studied extensively last decade, underpinning mechanisms remain elusive. In this review, we highlight emerging insights link to various related aging, such as sensing, maintenance proteostasis, autophagy, mitochondrial dysfunction,...
Abstract Despite its importance in human cancers, including colorectal cancers (CRC), oncogenic KRAS has been extremely challenging to target therapeutically. To identify potential vulnerabilities KRAS-mutated CRC, we characterize the impact of on cell surface intestinal epithelial cells. Here show that alters expression a myriad cell-surface proteins implicated diverse biological functions, and many surface-accessible therapeutic targets. Cell surface-based loss-of-function screens reveal...
Abstract Background Glutamine metabolism is a central metabolic pathway in cancer. Recently, reductive carboxylation of glutamine for lipogenesis has been shown to constitute key anabolic route cancer cells. However, little known regarding regulators the various pathways Methods The impact PGC-1α and ERRα on enzyme expression was assessed ERBB2+ breast cell lines with quantitative RT-PCR, chromatin immunoprecipitation, immunoblotting experiments. flux quantified using 13 C-labeled GC/MS...
Reprogramming of cellular metabolism plays a central role in fueling malignant transformation, and AMPK the PGC-1α/ERRα axis are key regulators this process. The intersection gene-expression binding-event datasets for breast cancer cells shows that activation significantly increases expression promotes binding ERRα to its cognate sites. Unexpectedly, data also reveal ERRα, concert with PGC-1α, negatively regulates several one-carbon genes, resulting substantial perturbations purine...
The relationship between nutrient starvation and mitochondrial dynamics is poorly understood. We find that cells facing amino acid display clear fusion as a means to evade mitophagy. Surprisingly, further supplementation of glutamine (Q), leucine (L), arginine (R) did not reverse, but produced stronger hyperfusion. Interestingly, the hyperfusion response Q + L R was dependent upon proteins Mfn1 Opa1 independent MTORC1. Metabolite profiling indicates addback replenishes nucleotide pools....
Notwithstanding that high rates of glucose uptake and glycolysis are common in neoplasia, pharmacological efforts to inhibit utilization for cancer treatment have not been successful. Recent evidence suggests addition classical transporters, sodium-glucose transporters (SGLTs) expressed by cancers. We therefore investigated the possibility SGLT inhibitors, which used type 2 diabetes, may exert antineoplastic activity limiting uptake. show SGLT2 inhibitor canagliflozin inhibits proliferation...
Despite the success of therapies targeting oncogenes in cancer, clinical outcomes are limited by residual disease that ultimately results relapse. This is often characterized non-genetic adaptive resistance, melanoma characterised altered metabolism. Here, we examine how targeted therapy reprograms metabolism BRAF-mutant cells using a genome-wide RNA interference (RNAi) screen and global gene expression profiling. Using this systematic approach demonstrate post-transcriptional regulation...
An increased level of phosphorylation eukaryotic translation initiation factor 2 subunit-α (eIF2α, encoded by EIF2S1; eIF2α-p) coupled with decreased guanine nucleotide exchange activity eIF2B is a hallmark the 'canonical' integrated stress response (c-ISR)1. It unclear whether impaired in human diseases including leukodystrophies2, which occurs absence eIF2α-p induction, synonymous c-ISR. Here we describe mechanism triggered activity, distinct from c-ISR, term split ISR (s-ISR). The s-ISR...
Abstract PRDM (PRDI-BF1 and RIZ homology domain containing) family members are sequence-specific transcriptional regulators involved in cell identity fate determination, often dysregulated cancer. The PRDM15 gene is of particular interest, given its low expression adult tissues overexpression B-cell lymphomas. Despite well characterized role stem biology during early development, the cancer remains obscure. Herein, we demonstrate that while largely dispensable for mouse somatic homeostasis...
Multiple myeloma (MM) is a hematological malignancy that emerges from antibody-producing plasma B cells. Proteasome inhibitors, including the US Food and Drug Administration-approved bortezomib (BTZ) carfilzomib (CFZ), are frequently used for treatment of patients with MM. Nevertheless, significant proportion MM refractory or develop resistance to this class which represents challenge in clinic. Thus, identifying factors determine potency proteasome inhibitors paramount importance bolster...
Emerging data suggest a significant cross-talk between metabolic and epigenetic programs. However, the relationship mechanistic target of rapamycin (mTOR), which is pivotal regulator, modifications remains poorly understood. Our results show that mTORC1 activation caused by abrogation its negative regulator tuberous sclerosis complex 2 (TSC2) coincides with increased levels histone modification H3K27me3 but not H3K4me3 or H3K9me3. This selective induction was mediated via 4E-BP-dependent...
One-carbon metabolism fuels the high demand of cancer cells for nucleotides and other building blocks needed increased proliferation. Although inhibitors this pathway are widely used to treat many cancers, their global impact on anabolic catabolic processes remains unclear. Using a combination real-time bioenergetics assays metabolomics approaches, we investigated effects methotrexate cellular metabolism. We show that treatment increases intracellular concentration metabolite AICAR,...
Mutations in genes encoding cytochrome c oxidase (mitochondrial complex IV) subunits and assembly factors [e.g., synthesis of 2 (SCO2)] are linked to severe metabolic syndromes. Notwithstanding that SCO2 is under transcriptional control tumor suppressor p53, the role mitochondrial IV dysfunction cancer metabolism remains obscure. Herein, we demonstrate loss HCT116 colorectal cells leads significant signaling perturbations. Specifically, abrogation increased NAD+ regenerating reactions...
Summary Emerging data suggest a significant cross-talk between metabolic and epigenetic programs. However, the relationship mechanistic target of rapamycin (mTOR) which is pivotal regulator cellular metabolism, modifications remains poorly understood. We thus explored impact modulating mTOR signaling on histone methylation, well-known modification. Our results showed that mTORC1 activation caused by abrogation TSC2 increased H3K27me3 but not H3K4me3 or H3K9me3. This appeared to be mediated...
Abstract Mitochondrial electron transport flavoprotein (ETF) insufficiency causes metabolic diseases known as a multiple acyl-CoA dehydrogenase deficiency (MADD). Although essential in muscle, we identified ETF (ETFDH) one of the most dispensable genes neoplasia, and its expression is reduced across human cancers. caused by decreased ETFDH limits flexibility OXPHOS fuel utilization, but paradoxically increases cancer cell bioenergetics accelerates neoplastic growth retrograde activation...
Emerging data suggest a significant cross-talk between metabolic and epigenetic programs. However, the relationship mechanistic target of rapamycin (mTOR) which is pivotal regulator cellular metabolism, modifications remains poorly understood. We thus explored impact modulating mTOR signaling on histone methylation, well-known modification. Our results showed that mTORC1 activation caused by abrogation TSC2 increased H3K27me3 but not H3K4me3 or H3K9me3. This appeared to be mediated via...
Abstract Reprogramming of energy metabolism is now considered a hallmark cancer. Deciphering molecular mechanisms underlying this process therefore necessary to understand malignant transformation and cancer progression, but also develop novel therapeutic tools. In the present study, our aim was discover potential links between two major pathways involved in breast cells: sensor AMPK (AMP-activated protein kinase) relationship with estrogen-related receptors (ERRα ERRγ) their coactivators...
Abstract Changes in gene expression, including those caused by epigenetic dysregulation, represent a hallmark of cancer. The mechanistic/mammalian Target Rapamycin (mTOR) is serine/threonine kinase that coordinates nutrient availability to the regulation cell growth and metabolism, which frequently perturbed mTOR exists two structurally functionally divergent complexes, complex 1 2 (mTORC1 2). mTORC1 regulates many metabolic pathways, serine-glycine-one carbon network (SGOC), pathway...