A5070625577- PARP inhibition in cancer therapy
- Histone Deacetylase Inhibitors Research
- Protein Degradation and Inhibitors
- PI3K/AKT/mTOR signaling in cancer
- Cancer-related Molecular Pathways
- Cell death mechanisms and regulation
- Ubiquitin and proteasome pathways
- Crystallization and Solubility Studies
- Tuberous Sclerosis Complex Research
- TGF-β signaling in diseases
- X-ray Diffraction in Crystallography
- Nuclear Receptors and Signaling
- Endoplasmic Reticulum Stress and Disease
- DNA Repair Mechanisms
- Cancer, Hypoxia, and Metabolism
- Autophagy in Disease and Therapy
- CAR-T cell therapy research
- Advanced Breast Cancer Therapies
- Bone health and treatments
- T-cell and Retrovirus Studies
- Cellular transport and secretion
- Protein Kinase Regulation and GTPase Signaling
- Epigenetics and DNA Methylation
- Phagocytosis and Immune Regulation
- Bone Metabolism and Diseases
Merck (Germany)
2009-2024
Peter MacCallum Cancer Centre
2004-2012
The University of Melbourne
2012
St Vincent's Hospital
2012
Monash University
2012
The University of Queensland
2012
Howard Hughes Medical Institute
2012
Cold Spring Harbor Laboratory
2012
National Center for Tumor Diseases
2008
German Cancer Research Center
2008
Histone deacetylase inhibitors (HDACi) can elicit a range of biological responses that affect tumor growth and survival, including inhibition cell cycle progression, induction cell-selective apoptosis, suppression angiogenesis, modulation immune responses, show promising activity against hematological malignancies in clinical trials. Using the Emu-myc model B lymphoma, we screened tumors with defined genetic alterations apoptotic pathways for therapeutic responsiveness to HDACi vorinostat....
Cytotoxic activities of several Golgi-dispersing compounds including AMF-26/M-COPA, brefeldin A and golgicide have previously been shown to induce autophagy or apoptosis. Here, we demonstrate that these Golgi disruptors also trigger ferroptosis, a non-apoptotic form cell death characterized by iron-dependent oxidative degradation lipids. Inhibitors ferroptosis not only counteract death, but they protect from dispersal inhibition protein secretion in response stress agents. Furthermore, the...
Histone deacetylase inhibitors (HDACi) are a promising new class of chemotherapeutic drug currently in early phase clinical trials. A large number structurally diverse HDACi have been purified or synthesised that mostly inhibit the activity all eleven I and II HDACs. While these agents demonstrate many features required for anti-cancer such as low toxicity against normal cells an ability to tumor cell growth survival at nanomolar concentrations, their mechanisms action largely unknown....
Histone deacetylase inhibitors (HDACi) and agents such as recombinant tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) agonistic anti-TRAIL receptor (TRAIL-R) antibodies are anticancer that have shown promise in preclinical settings early phase clinical trials monotherapies. Although HDACi activators of the TRAIL pathway different molecular targets mechanisms action, they share ability to induce cell-selective apoptosis. The expression TRAIL-R death receptors 4 5 (DR4/DR5),...
Granzyme B, a protease released from cytotoxic lymphocytes, has been proposed to induce target cell death by cleaving and activating the pro-apoptotic Bcl-2 family member Bid. It also that granzyme B can caspases directly, caspase substrates, and/or several non-caspase substrates. The relative importance of Bid in B-induced therefore remained unclear. Here we report cells isolated various tissues Bid-deficient mice were resistant death. Consistent with role regulating mitochondrial outer...
MYC deregulation is common in human cancer. IG-MYC translocations that are modeled Eμ-Myc mice occur almost all cases of Burkitt lymphoma as well other B-cell lymphoproliferative disorders. Deregulated expression results increased mTOR complex 1 (mTORC1) signaling. As tumors with mTORC1 activation sensitive to inhibition, we used everolimus, a potent and specific inhibitor, test the requirement for initiation maintenance lymphoma. Everolimus selectively cleared premalignant B cells from bone...
The majority of breast cancers metastasizing to bone secrete parathyroid hormone-related protein (PTHrP). PTHrP induces local osteolysis that leads activation matrix-borne transforming growth factor β (TGFβ). In turn, TGFβ stimulates expression and, thereby, accelerates destruction. We studied the mechanism by which activates in invasive MDA-MB-231 cancer cells. demonstrate TGFβ1 up-regulates specifically level P3 promoter-derived RNA an actinomycin D-sensitive fashion. Transient...
Abstract Histone deacetylase inhibitors (HDACi) are compounds that target the epigenome and cause tumor cell-selective apoptosis. A large number of these agents have different chemical structures can multiple HDACs being testing in clinical trials vorinostat is now an approved drug for treatment cutaneous T-cell lymphoma. Although showing promise hematologic malignancies, it possible drugs may mechanistic, biological, therapeutic activities. When comparing HDACi belonging to hydroxamic acid...
Tether complexes play important roles in endocytic and exocytic trafficking of lipids proteins. In yeast, the multisubunit transport protein particle (TRAPP) tether regulates endoplasmic reticulum (ER)-to-Golgi intra-Golgi is also implicated autophagy. addition, TRAPP complex acts as a guanine nucleotide exchange factor (GEF) for Ypt1, which homologous to human Rab1a Rab1b. Here, we show that TRAPPC13 other subunits are critically involved survival response several Golgi-disrupting agents....
The secretory pathway is a major determinant of cellular homoeostasis. While research into stress signaling has so far mostly focused on the endoplasmic reticulum (ER), emerging data suggest that Golgi itself serves as an important hub capable initiating responses. To systematically identify novel mediators, we performed transcriptomic analysis cells exposed to three different pharmacological compounds known elicit fragmentation: brefeldin A, golgicide and monensin. Subsequent gene-set...
The Golgi apparatus is part of the secretory pathway and central importance for modification, transport sorting proteins lipids. ADP ‐ribosylation factors, whose activation can be blocked by brefeldin A ( BFA ), play a major role in functioning network regulation membrane traffic are also involved proliferation migration cancer cells. Due to high cytotoxicity poor bioavailability, has not passed preclinical stage drug development. Recently, AMF‐26 golgicide have been described as novel...
Disruption of the Golgi apparatus can induce a distinct form programmed cell death that has not been thoroughly characterized. We found pharmacological application stress leads to induction receptors (DRs) 4 and 5. DR4 appears be primarily responsible for initiation downstream stress, whereas DR5 seems more important triggered by endoplasmic reticulum (ER) in specific cancer lines. DR either or ER mainly causes intracellular accumulation presumably at Golgi, rather than increased expression...
Metastatic clear cell renal carcinomas (ccRCCs) are resistant to DNA-damaging chemotherapies, limiting therapeutic options for patients whose tumors tyrosine kinase inhibitors and/or immune checkpoint therapies. Here we show that mouse and human ccRCCs were frequently characterized by high levels of endogenous DNA damage cultured ccRCC cells exhibited intact cellular responses chemotherapy-induced damage. We identify pharmacological inhibition the damage-sensing ataxia telangiectasia...
Abstract Energy and biomass production in cancer cells are largely supported by aerobic glycolysis what is called the Warburg effect. The process regulated key enzymes, among which phosphofructokinase PFK‐2 plays a significant role producing fructose‐2,6‐biphosphate; most potent activator of rate‐limiting step performed PFK‐1. Herein, synthesis, biological evaluation structure–activity relationship novel inhibitors 6‐phosphofructo‐2‐kinase/fructose‐2,6‐biphosphatase 3 (PFKFB3), ubiquitous...
We have previously shown that PKC inhibitors interfere with the Ets1/Smad3-dependent regulation of parathyroid hormone-related protein (PTHrP) P3 promoter activity by TGFbeta in invasive MDA-MB-231 breast cancer cells. By examining expression a variety cell lines, level PKCalpha was found to be much higher Ets1-expressing and MDA-MB-435 cells than Ets1-deficient MCF-7 SK-BR3 No correlation Ets1 other subtypes (PKCbeta1, PKCbeta2, PKCdelta or PKCepsilon) could observed. In contrast cells,...
Parathyroid hormone-related protein (PTHrP) promotes the metastatic potential and proliferation of breast cancer cells, acts anti-apoptotically. In invasive MDA-MB-231 transforming growth factor beta-regulated PTHrP synthesis is mediated by an Ets1/Smad3-dependent activation P3 promoter. present study, we studied regulation expression in non-invasive, Ets1-deficient beta-resistant MCF-7 cells. We found PMA to be a strong stimulator P3-dependent Mitogen-activated kinase...
The Golgi apparatus is increasingly recognized as a major hub for cellular signaling and involved in numerous pathologies, including neurodegenerative diseases cancer. study of stress-induced pathways relies on the selectivity available tool compounds which currently only few are known. To discover novel Golgi-fragmenting agents, transcriptomic profiles cells treated with brefeldin A, golgicide or monensin were generated compared database gene expression from other bioactive small molecules....