A5023223096- Trace Elements in Health
- Iron Metabolism and Disorders
- Cancer, Hypoxia, and Metabolism
- PI3K/AKT/mTOR signaling in cancer
- Virus-based gene therapy research
- Cancer, Lipids, and Metabolism
- Cell death mechanisms and regulation
- Lung Cancer Treatments and Mutations
- Genomics, phytochemicals, and oxidative stress
- Metabolomics and Mass Spectrometry Studies
- Biochemical and Molecular Research
- Hippo pathway signaling and YAP/TAZ
- RNA regulation and disease
- HER2/EGFR in Cancer Research
- Cancer Genomics and Diagnostics
- Acute Myeloid Leukemia Research
- Glutathione Transferases and Polymorphisms
- Redox biology and oxidative stress
- Epigenetics and DNA Methylation
- Synthesis and biological activity
- Protein Degradation and Inhibitors
- Lipid metabolism and biosynthesis
- Autophagy in Disease and Therapy
- RNA modifications and cancer
- Signaling Pathways in Disease
Peter MacCallum Cancer Centre
2018-2024
The University of Melbourne
2018-2024
Selecta Biosciences (United States)
2023-2024
Texas Neurology
2023
The University of Texas Health Science Center at Houston
2022
Bluefield State College
2021
Beth Israel Deaconess Medical Center
2011-2018
Harvard University
2013-2018
GlaxoSmithKline (United States)
2011-2013
University of Otago
2006-2011
Breast carcinoma is the leading cause of cancer-related mortality in women worldwide, with an estimated 1.38 million new cases and 458,000 deaths 2008 alone. This malignancy represents a heterogeneous group tumours characteristic molecular features, prognosis responses to available therapy. Recurrent somatic alterations breast cancer have been described, including mutations copy number alterations, notably ERBB2 amplifications, first successful therapy target defined by genomic aberration....
Whole-genome CRISPR screens identify resistance to TNF-mediated killing by T and NK cells as a tumor immune evasion mechanism.
Chemotherapy resistance is a major barrier to the treatment of triple-negative breast cancer (TNBC), and strategies circumvent are required. Using in vitro vivo metabolic profiling TNBC cells, we show that an increase abundance pyrimidine nucleotides occurs response chemotherapy exposure. Mechanistically, elevation induced by dependent on increased activity de novo synthesis pathway. Pharmacologic inhibition sensitizes cells genotoxic agents exacerbating DNA damage. Moreover, combined with...
The liver exhibits a remarkable capacity to regenerate following injury. Despite this unique attribute, toxic injury is leading cause of failure. temporal processes by which the senses and initiates regeneration remain unclear. Here, we developed transgenic zebrafish model wherein hepatocyte-specific expression uracil phosphoribosyltransferase (UPRT) enabled implementation SLAM-ITseq investigate nascent transcriptome during initiation regeneration. Using approach, identified rapid metabolic...
Heterozygously expressed single-point mutations in isocitrate dehydrogenase 1 and 2 (IDH1 IDH2, respectively) render these dimeric enzymes capable of producing the novel metabolite α-hydroxyglutarate (αHG). Accumulation αHG is used as a biomarker for number cancer types, helping to identify tumors with similar IDH mutations. With IDH1, it has been shown that one role mutation increase rate conversion from αKG αHG. To improve our understanding function this mutation, we have detailed kinetics...
Abstract Internal tandem duplication of the FMS-like tyrosine kinase 3 gene (FLT3-ITD) occurs in 30% all acute myeloid leukemias (AML). Limited clinical efficacy FLT3 inhibitors highlights need for alternative therapeutic modalities this subset disease. Using human and murine models FLT3-ITD–driven AML, we demonstrate that FLT3-ITD promotes serine synthesis uptake via ATF4-dependent transcriptional regulation genes de novo biosynthesis pathway neutral amino acid transport. Genetic or...
Abstract Glutamine is a conditionally essential nutrient for many cancer cells, but it remains unclear how consuming glutamine in excess of growth requirements confers greater fitness to glutamine-addicted cancers. By contrasting two breast subtypes with distinct dependencies, we show that glutamine-indispensable triple-negative (TNBC) cells rely on non-canonical glutamine-to-glutamate overflow, carbon routed once through the TCA cycle. Importantly, this single-pass glutaminolysis increases...
The maintenance of redox and metabolic homeostasis is integral to embryonic development. Nuclear factor erythroid 2-related 2 (NRF2) a stress-induced transcription that plays central role in the regulation balance cellular metabolism. Under homeostatic conditions, NRF2 repressed by Kelch-like ECH-associated protein 1 (KEAP1). Here, we demonstrate Keap1 deficiency induces Nrf2 activation postdevelopmental lethality. Loss viability preceded severe liver abnormalities characterized an...
Isothiocyanates are a class of phytochemicals with widely reported anti-cancer and anti-inflammatory activity. However, knowledge their activity at molecular level is limited. The objective this study was to identify biological targets phenethyl isothiocyanate (PEITC) using an affinity purification approach. An analogue PEITC synthesized enable conjugation solid-phase resin. pleiotropic cytokine macrophage migration inhibitory factor (MIF) the major protein captured from cell lysates....
Significance Dietary selenium and selenoproteins play important roles in regulating redox processes that impact human health. The genome includes 25 genes for selenoproteins, which have diverse homeostasis, thyroid hormone metabolism, endoplasmic reticulum quality control, transport, other functions. Selenoprotein H ( seph ) is a recently identified nucleolar oxidoreductase with DNA-binding properties whose function not well understood. In this work, we used unique combination of unbiased...
Recent evidence has highlighted the importance of employing cell culture media designed to reproduce physiological metabolic environment in vitro. Here, we utilize medium Plasmax examine impact nutrient availability on model human hepatocyte line, HepG2. Incubation HepG2 cells suppressed a transcriptional program driven by Hepatocyte Nuclear Factor 4 (HNF4A), master regulator identity. Given that were originally isolated from patient with hepatoblastoma, this suggests reversion native state...
Toxic liver injury is a leading cause of failure and death because the organ's inability to regenerate amidst massive cell death, few therapeutic options exist. The mechanisms coordinating damage protection repair are poorly understood. Here, we show that S-nitrosothiols regulate growth during development after in vivo; zebrafish, nitric-oxide (NO) enhanced formation independently cGMP-mediated vasoactive effects. After acetaminophen (APAP) exposure, inhibition enzymatic regulator...
Resistance to cytotoxic chemotherapy drugs, including doxorubicin, is a significant obstacle the effective treatment of breast cancer. Here, we have identified mechanism by which PI3K/Akt pathway mediates resistance doxorubicin. In addition inducing DNA damage, doxorubicin triggers sustained activation Akt signaling in cancer cells. We show that contributes such PI3K or inhibitors sensitize cells identify MERIT40, component BRCA1-A damage repair complex, as an substrate phosphorylated...
Cancer cell metabolism is increasingly recognized as providing an exciting therapeutic opportunity. However, a drug that directly couples targeting of metabolic dependency with the induction death in cancer cells has largely remained elusive. Here we report drug-like small-molecule ironomycin reduces mitochondrial iron load, resulting potent disruption metabolism. Ironomycin promotes recruitment and activation BAX/BAK, but outer membrane permeabilization (MOMP) does not lead to apoptotic...
Despite significant progress, our understanding of how specific oncogenes transform cells is still limited and likely underestimates the complexity downstream signalling events. To address this gap, we use mass spectrometry-based chemical proteomics to characterize global impact an oncogene on expressed kinome, then functionally annotate regulated kinases. As example, identify 63 protein kinases exhibiting altered expression and/or phosphorylation in Src-transformed mammary epithelial cells....
Mitochondrial peroxiredoxin 3 (Prx 3) is rapidly oxidized in cells exposed to phenethyl isothiocyanate (PEITC) and auranofin (AFN), but the mechanism of oxidation unclear. Using HL‐60 deplete mitochondrial DNA we show that cytotoxicity requires a functional respiratory chain. Thioredoxin reductase (TrxR) could be inhibited by up 90% without direct 3. However, inhibition thioredoxin promoted combination with or antimycin A. We conclude rapid occurs as consequence increased oxidant production from