The Functional Role of Pdk1 in Arnt Oncogene-Regulated Tumorigenesis and Tumor Progression

For a long time, the Warburg effect has been used to state the specific event that occurs in tumor cells. A growing number of reports show that metabolic enzymes 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 presents much higher levels in cancer cells than in normal cells to correlate with the enhancement of cancer progression, has been introduced. However, the detailed mechanisms that individual enzyme regulates tumorigenesis remains to be clarified. In addition, how could be metabolic enzymes expression disregulated during tumorigenesis that is also not clear. Here we seek to understand how tumor proliferation, metastasis and drug-resistance are regulated by the expression of metabolic enzymes. Those areas of study are significant because they are associated with the challenge of cancer therapy. While the role of ARNT oncogene in the regulation of metabolic enzymes expression has not been examined in animal study and human tumor tissues, in our preliminary results, the expression of PDK1 induced by ARNT was confirmed in tumor cell lines, and the inhibition of PDK1 blocked ARNT knockdown-induced tumor metastasis, presenting an opportunity to gain a complete understanding of how the effect of metabolic enzymes on ARNT regulated tumor development and treatment. This project is expected to provide novel insights into an unexplored area of ARNT-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 specific aims to be investigated in this project are: 1. Study mechanisms involved in ARNT-induced PDK1 expression and mitochondria dysregulation in cancer cells 2. Clarify PDK1 expression in the correlation with ARNT-induced tumor proliferation and -inhibited metastasis 3. Identify the potential role of ARNT-induced PDK1 in the regulation of drug resistance