For a long time, the Warburg effect has been used to state the specific event that occurs in tumor cells. In addition to regulating aerobic glycolysis, interestingly, a growing number of reports show that metabolic enzymes (e.g. lactate dehydrogenase, pyruvate kinase M2, hexokinase 2 and pyruvate dehydrogenase kinase 3) also play important roles in mediating tumor development in recent years. These indicate that metabolic enzymes not only play important roles in glycolysis and glutamine metabolism may also present novel targets for cancer therapy. Thus, the concept of oncometabolites, which present much higher levels in cancer cells than in normal cells to correlate with the enhancement of cancer progression, has been introduced. However, the detail mechanisms that individual enzyme regulates tumorigenesis remains to be clarified. In addition, how could be metabolic enzymes expression disregulated during tumorigenesis that is also completely unknown. Here we seek to understand how growth factor (e.g. EGF) signaling controls tumor proliferation, metastasis and drug-resistance by regulating the expression of metabolic enzymes (e.g. PDK1 and HK-2). These areas of study are significant because they are associated with the challenge of cancer therapy. While the correlation between EGFR and metabolic enzymes expression has not been examined in animal study and human tumor tissues, in our preliminary results, the expression of PDK1 and HK-2 induced by EGF was confirmed in tumor cell lines, and the reduction of PDK1 and HK-2 expression in ARNT knockdown cells was more sensitive to cisplatin-induced cell death, presenting an opportunity to gain a complete understanding of how the effect of metabolic enzymes on EGF regulated tumor development and treatment. Data obtained from in vitro cancer cell model will be verified by using Kras-induced lung tumorigenesis of in vivo mouse model. This project is expected to provide novel insights into an unexplored area of EGF-regulated gene expression of metabolic enzymes in cancer that will not only fuel a better understanding of this process, but will facilitate the development of more therapeutic targets in cancer. The three overlapping areas to be investigated in this project are: 1. Study mechanisms involved in the regulation of PDK1 and HK-2 expression in EGF-treated various cancer cell lines 2. Clarify PDK1 and HK-2 expression in the correlation with EGF-induced tumor proliferation and metastasis 3. Identify the potential role of PDK1 and HK-2 in the regulation of drug resistance
|Effective start/end date||8/1/15 → 7/31/16|
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