Graduate Thesis Or Dissertation


Natural Products as Pharmacological Tools to probe Mitochondrial and Secretory Function in Cancer Cells Public Deposited

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  • Cancer is the second leading cause of death in the United States. To date, over 60% of current anticancer drugs were inspired by the discovery of chemical structure from nature, commonly known as a natural product. This work represents the biological characterization of several marine natural product compounds and their use as pharmacological tools to study mitochondrial and secretory functions in human cancer cells. The natural product mandelalide A was recently found to be a direct inhibitor of ATP synthase. We revealed that mandelalide A induces transient activation of the AMP-activated protein kinase pathway in an LKB1-dependent manner in several human cancer cells. Mandelalide A induces a synergistic affect in combination with first-line antitumor agents erlotinib and paclitaxel on EGFR mutant non-small cell lung cancer cells. Another new class of cytotoxic marine natural products, coibamide A and apratoxin A, were found to use autophagy-related protein 5 (ATG5) to promote cell death signaling. Mouse embryonic fibroblasts (MEFs) with a functional autophagy pathway were more sensitive to these rare natural product compounds which are inhibitors of the secretory pathway. The secretory pathway is a potentially novel, and future target for cancer therapy. We developed a workflow for discovery of new secretion inhibitors by combining a functional Gluc secretion assay with recognized cell viability assays. We used this workflow to identify 6 small molecules out of 3906 screened, and characterized the inhibitory activity of coibamide A in this screen. Using a cellular thermal shift assay, we identified the translocon protein Sec61 alpha as a direct binding target of coibamide A. We discovered that the resident endoplasmic reticulum (ER) chaperone protein glucose regulated protein 78 (GRP78) is a critical, indirect target of coibamide A. High basal expression of GRP78 and distribution to cellular compartment outside the ER has been increasingly associated with human cancers. We identified upregulation of GRP78 expression in canine osteosarcoma cells and investigated the use of an anti-cancer drug OSU-03012 to target GPR78 overexpression in these cells. In summary, we concluded that activation of AMPK pathway by mandelalide A-like compounds, and inhibition of secretory function or secretory client proteins by coibamide A-like compounds could be beneficial as therapeutical strategies in cancer treatment.
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  • 2018-06-16 to 2020-07-16



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