PhD student , University of Sydney
Cancer cells require high amount of energy to grow and proliferate. My research looks at the effect of a novel anti cancer drug on the energy homeostasis pathway in the cells, and how we can exploit this for better future treatment options.
Abstract: Cancer cells have a greater need for energy and a ready supply of the building blocks necessary for the synthesis of macromolecules (nucleotides, protein, lipids) in order to duplicate genome and biomass. The hypothesis can be postulated that those precursors for synthetic processes, which can only be furnished by glycolysis, cannot be sufficiently recruited from external sources (the blood stream) and that glycolysis is necessarily markedly activated. It can also be hypothesized that the Krebs cycle, which also furnishes precursors for macromolecule synthesis to meet the requirements of proliferating cells, is depleted of intermediates. In view of its cyclic nature requiring not only pyruvate but also oxalacetate as the "last" metabolite of the reaction sequence for its sustenance, the Krebs cycle may be partially inactivated. While anaplerotic reactions and other sources (amino acids and fatty acids) could supply the cycle with intermediates, those pathways constitute futile cycles for amino and fatty acids as they would be partially degraded in the cycle and the intermediates thus obtained would be exported into the cytoplasm for synthetic processes with no advantage for the cell. It is also hypothesized that glutamine, an important fuel for cancer cells and playing a critical role in anaplerosis, may not contribute to reinforce the cycle; malate and α-ketoglutarate, two products of glutamine metabolism, might be exported from the mitochondria as precursors of biosynthetic pathways. It is possible then that malate, used for NADPH production required in the biosynthetic pathways, and glycerol-phosphate, too used for biosynthetic purposes (lipid biosynthesis), are unable to sustain the mitochondrial redox shuttles reducing the respiratory capacity of the mitochondria. Low shuttle capacity implies that NADH generated by glycolysis needs to be continuously re-oxidized in the cytoplasm via lactate dehydrogenase to maintain glycolysis fully activated, causing the abnormal lactate production observed in cancer. The paper goes onto discuss the essential role of glucose in cancer cell proliferation also in inducing the Crabtree effect. It is finally hypothesized that respiration inhibition after cancer cells have been supplied with glucose is due to reactivation in a suited medium of biosynthetic pathways with the consequences described above.
Pub.: 10 Jul '12, Pinned: 28 Aug '17
Abstract: AMPK is a metabolic sensor that helps maintain cellular energy homeostasis. Despite evidence linking AMPK with tumor suppressor functions, the role of AMPK in tumorigenesis and tumor metabolism is unknown. Here we show that AMPK negatively regulates aerobic glycolysis (the Warburg effect) in cancer cells and suppresses tumor growth in vivo. Genetic ablation of the α1 catalytic subunit of AMPK accelerates Myc-induced lymphomagenesis. Inactivation of AMPKα in both transformed and nontransformed cells promotes a metabolic shift to aerobic glycolysis, increased allocation of glucose carbon into lipids, and biomass accumulation. These metabolic effects require normoxic stabilization of the hypoxia-inducible factor-1α (HIF-1α), as silencing HIF-1α reverses the shift to aerobic glycolysis and the biosynthetic and proliferative advantages conferred by reduced AMPKα signaling. Together our findings suggest that AMPK activity opposes tumor development and that its loss fosters tumor progression in part by regulating cellular metabolic pathways that support cell growth and proliferation.
Pub.: 01 Jan '13, Pinned: 28 Aug '17
Abstract: The PRKAA1 gene encodes the catalytic α-subunit of 5′ AMP-activated protein kinase (AMPK). AMPK is a cellular energy sensor that maintains energy homeostasis within the cell and is activated when the AMP/ATP ratio increases. When activated, AMPK increases catabolic processes that increase ATP synthesis and inhibit anabolic processes that require ATP. Additionally, AMPK also plays a role in activating autophagy and inhibiting energy consuming processes, such as cellular growth and proliferation. Due to its role in energy metabolism, it could act as a potential target of many therapeutic drugs that could be useful in the treatment of several diseases, for example, diabetes. Moreover, AMPK has been shown to be involved in inhibiting tumour growth and metastasis, and has also been implicated in the pathology of neurodegenerative and cardiac disorders. Hence, a better understanding of AMPK and its role in various pathological conditions could enable the development of strategies to use it as a therapeutic target.
Pub.: 05 Jun '14, Pinned: 25 Aug '17
Abstract: Adenosine monophosphate-activated protein kinase (AMPK) is a cellular energy sensor, which once activated, plays a role in several processes within the cell to restore energy homeostasis. The protein enhances catabolic pathways, such as β-oxidation and autophagy, to generate ATP, and inhibits anabolic processes that require energy, including fatty acid, cholesterol, and protein synthesis. Due to its key role in the regulation of critical cellular pathways, deregulation of AMPK is associated with the pathology of many diseases, including cancer, Wolff-Parkinson-White syndrome, neurodegenerative disorders, diabetes, and metabolic syndrome. In fact, AMPK is a target of some pharmacological agents implemented in the treatment of diabetes (metformin and thiazolidinediones) as well as other naturally derived products, such as berberine, which is used in traditional medicine. Due to its critical role in the cell and the pathology of several disorders, research into developing AMPK as a therapeutic target is becoming a burgeoning and exciting field of pharmacological research. A profound understanding of the regulation and activity of AMPK would enhance its development as a promising therapeutic target.
Pub.: 26 Nov '14, Pinned: 25 Aug '17
Abstract: Adenosine monophosphate-activated protein kinase (AMPK) is a cellular energy sensor that monitors ATP levels. There is also evidence that AMPK has onco-suppressive properties. Iron plays a crucial role in cellular energy transducing pathways and tumor cell proliferation. Therefore, metals (e.g., iron) could play an important role in the regulation of AMPK-dependent pathways. Hence, this investigation examined the effect of the iron and copper chelator and potent anti-cancer agent, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT), on the AMPK-mediated pathway. These studies demonstrated that Dp44mT, which forms intracellular redox-active complexes with iron and copper, significantly activated AMPK (i.e., p-AMPK/AMPK ratio) in 5 different tumor cell-types. Furthermore, examination of the Dp44mT-metal complexes demonstrated that the effect of Dp44mT on AMPK was due to a dual mechanism: (1) its ability to chelate metal ions; and (2) the generation of reactive oxygen species (ROS). The activation of the AMPK-pathway by Dp44mT was mediated by the upstream kinase, liver kinase B1 (LKB1) that is a known tumor suppressor. Moreover, using AMPKα1-selective silencing, we demonstrated that Dp44mT activated AMPK, resulting in inhibition of acetyl CoA carboxylase 1 (ACC1) and raptor, and activation of Unc-51 like kinase (ULK1). These effects are vital for inhibition of fatty acid synthesis, suppression of protein synthesis and autophagic activation, respectively. Together, this AMPK-mediated repair response aims to rescue the loss of metal ions via chelation and the induction of cytotoxic damage mediated by redox cycling of the Dp44mT-metal ion complex. In conclusion, this study demonstrates for the first time that chelators target the AMPK-dependent pathway.
Pub.: 19 Sep '16, Pinned: 25 Aug '17