A5019943792- Mitochondrial Function and Pathology
- Acute Myeloid Leukemia Research
- Histone Deacetylase Inhibitors Research
- Ubiquitin and proteasome pathways
- Blood properties and coagulation
- Epigenetics and DNA Methylation
- Protease and Inhibitor Mechanisms
- Peptidase Inhibition and Analysis
- RNA Interference and Gene Delivery
- Cancer therapeutics and mechanisms
- Cancer-related gene regulation
- Protein Degradation and Inhibitors
- Chemical Synthesis and Analysis
- Cancer, Hypoxia, and Metabolism
- Metabolomics and Mass Spectrometry Studies
- Wnt/β-catenin signaling in development and cancer
- interferon and immune responses
- Immune cells in cancer
- Drug Transport and Resistance Mechanisms
- Blood Coagulation and Thrombosis Mechanisms
- Mosquito-borne diseases and control
- Trace Elements in Health
- Machine Learning in Bioinformatics
- Kruppel-like factors research
- Heme Oxygenase-1 and Carbon Monoxide
Princess Margaret Cancer Centre
2016-2025
University Health Network
2014-2025
Ontario Institute for Cancer Research
2011-2014
The University of Kansas Cancer Center
2011
The mitochondrial caseinolytic protease P (ClpP) plays a central role in protein quality control by degrading misfolded proteins. Using genetic and chemical approaches, we showed that hyperactivation of the selectively kills cancer cells, independently p53 status, selective degradation its respiratory chain substrates disrupts structure function, while it does not affect non-malignant cells. We identified imipridones as potent activators ClpP. Through biochemical studies crystallography,...
Yeasty HIPHOP In order to identify how chemical compounds target genes and affect the physiology of cell, tests perturbations that occur when treated with a range pharmacological chemicals are required. By examining haploinsufficiency profiling (HIP) homozygous (HOP) chemogenomic platforms, Lee et al. (p. 208 ) analyzed response yeast thousands different small molecules, genetic, proteomic, bioinformatic analyses. Over 300 were identified targeted 121 within 45 cellular signature networks....
Abstract Despite high initial response rates, acute myeloid leukemia (AML) treated with the BCL-2–selective inhibitor venetoclax (VEN) alone or in combinations commonly acquires resistance. We performed gene/protein expression, metabolomic and methylation analyses of isogenic AML cell lines sensitive resistant to VEN, identified activation RAS/MAPK pathway, leading increased stability higher levels MCL-1 protein, as a major acquired mechanism VEN sustained survival maintained mitochondrial...
Excessive signaling from the Wnt pathway is associated with numerous human cancers. Using a high throughput screen designed to detect inhibitors of Wnt/β-catenin signaling, we identified series acyl hydrazones that act downstream β-catenin destruction complex inhibit both Wnt-induced and cancer-associated constitutive via destabilization β-catenin. We found these bind iron in vitro intact cells chelating activity required abrogate block growth colorectal cancer cell lines signaling. In...
The antimycotic ciclopirox olamine is an intracellular iron chelator that has anticancer activity in vitro and vivo. We developed oral formulation of conducted the first-in-human phase I study this drug patients with relapsed or refractory hematologic malignancies (Trial registration ID: NCT00990587). Patients were treated 5-80 mg/m² once daily for five days 21-day treatment cycles. Pharmacokinetic pharmacodynamic companion studies performed a subset patients. Following definition half-life...
Abstract Acute myeloid leukemia ( AML ) cells meet the higher energy, metabolic, and signaling demands of cell by increasing mitochondrial biogenesis protein translation. Blocking synthesis through genetic chemical approaches kills human at all stages development in vitro vivo. Tigecycline is an antimicrobial that we found inhibits cells. Therefore, conducted a phase 1 dose‐escalation study tigecycline administered intravenously daily 5 7 days for 2 weeks to patients with . A total 27 adult...
Tigecycline is a broad-spectrum, first-in-class glycylcycline antibiotic currently used to treat complicated skin and intra-abdominal infections, as well community-acquired pneumonia. In addition, we have demonstrated that tigecycline also has in vitro vivo activity against acute myeloid leukemia (AML) due its ability inhibit mitochondrial translation. relatively unstable after reconstitution, this instability may limit the use of drug ambulatory infusions for treatment infection prevent...
Boronic acids have attracted the attention of synthetic and medicinal chemists due to boron's ability modulate enzyme function. Recently, we demonstrated that boron-containing amphoteric building blocks facilitate discovery bioactive aminoboronic acids. Herein, augmented this capability with a de novo library design virtual screening platform modified for covalent ligands. This technique has allowed us rapidly identify series α-aminoboronic as first inhibitors human ClpXP, which is...
Neurolysin (NLN) is a zinc metallopeptidase whose mitochondrial function unclear. We found that NLN was overexpressed in almost half of patients with acute myeloid leukemia (AML), and inhibition selectively cytotoxic to AML cells stem while sparing normal hematopoietic cells. Mechanistically, interacted the respiratory chain. Genetic chemical impaired oxidative metabolism disrupted formation chain supercomplexes (RCS). Furthermore, known RCS regulator, LETM1, LETM1 complex formation. were...
ClpXP is a two-component mitochondrial matrix protease. The caseinolytic peptidase chaperone subunit X (ClpX) recognizes and translocates protein substrates into the degradation chamber of protease P (ClpP) for proteolysis. degrades damaged respiratory chain proteins necessary cancer cell survival. Despite critical role in quality control, specific degrons, or modifications that tag substrate by human ClpXP, are still unknown. We demonstrated phosphorylated serine (pSer) targets to ClpX...
Abstract ClpXP is an AAA+ protease located in mitochondria matrix. In human, degrades damaged respiratory chain proteins and essential for acute myeloid leukemia (AML) cell survival. This complex consists of the tetradecameric ClpP regulatory particles ClpX. bacteria, targets substrates with a co-translationally added SsrA sequence. However, human lacks this tag degron remain unidentified. Notably, bacterial homologues degrade phosphorylated arginine (pArg). We hypothesized that amino acids...
Abstract Almost all mitochondrial proteins are encoded by nuclear DNA, translated in the cytosol, and imported into mitochondria. Once inside mitochondria, these unfolded, aggregation prone precursors processed folded mature forms. Failure to properly process fold newly results formation of toxic aggregates. To counter stress from proteins, cells developed unfolded protein response (UPRmt), a conserved pathway which activates transcription proteases chaperones degrade There no UPRmt gene...
Recently, we demonstrated that the anti-bacterial agent tigecycline preferentially induces death in leukemia cells through inhibition of mitochondrial protein synthesis. Here, sought to understand mechanisms resistance by establishing a cell line resistant drug. TEX were treated with increasing concentrations over 4 months and population (RTEX+TIG) was selected. Compared wild type cells, RTEX+TIG had undetectable levels mitochondrially translated proteins Cox-1 Cox-2, reduced oxygen...
Human ClpP protease contributes to mitochondrial protein quality control by degrading misfolded proteins. is overexpressed in cancers such as acute myeloid leukemia (AML), where its inhibition leads the accumulation of damaged respiratory chain subunits and cell death. Conversely, hyperactivating with small-molecule activators, recently discovered ONC201, disrupts degradation impairs respiration cancer cells. Despite critical role human health, mechanism underlying structural functional...
Mitochondrial DNA encodes 13 proteins that comprise components of the respiratory chain maintain oxidative phosphorylation. The replication mitochondrial is performed by sole polymerase γ. As acute myeloid leukemia (AML) cells and stem have an increased reliance on phosphorylation, we sought to evaluate γ inhibitors in AML. thymidine dideoxynucleoside analog, alovudine, inhibitor In AML cells, alovudine depleted DNA, reduced encoded proteins, decreased basal oxygen consumption, cell...