A pinboard by
Sukriti Krishan

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.


Energy metabolism in cancer cells: how to explain the Warburg and Crabtree effects?

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

The Anticancer Agent, Di-2-Pyridylketone 4,4-Dimethyl-3-Thiosemicarbazone (Dp44mT), Up-Regulates the AMPK-Dependent Energy Homeostasis Pathway in Cancer Cells.

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