Date on Master's Thesis/Doctoral Dissertation
Biochemistry and Molecular Biology
Ellis, Steven R.
Committee Co-Chair (if applicable)
6-phosphofructo-2-kinase; PFKFB3; Autophagy; 3PO
Metabolism; Cancer cells
Altered metabolism has long been recognized as a defining characteristic of tumor cells. The increased glycolytic phenotype, an observation credited to Otto Warburg in 1956, is almost universal for cancer cells, making metabolic enzymes attractive targets for cancer therapy. However, anti-metabolic drugs, thus far, have not lived up to expectations as stand-alone agents to treat this disease. Unlike glycolytic enzymes that directly catabolize glucose to pyruvate, the family of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases (PFKFBs) control the conversion of fructose-6-phosphate to and from fructose-2,6-bisphosphate, a key regulator of the glycolytic enzyme phosphofructokinase-1 (PFK-1). One isoform, PFKFB3, has been shown to be highly expressed by human cancer cells and a specific PFKFB3 small molecule inhibitor, (3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one [3PO] is currently being developed for clinical use. However, the effectiveness of current chemotherapeutics is limited by the development of drug resistance, which is especially problematic for antimetabolic drugs where the starvation state activates a variety of survival mechanisms within the cell that contribute to resistance. One such mechanism used by all cells to survive nutrient-poor conditions is the activation of autophagy, the process of cellular self-catabolism. Autophagic induction allows for the continued generation of biosynthetic intermediates that can be used for energy generation and critical metabolic processes while also ensuring prompt disposal of damaged and malfunctioning organelles before they cause cellular harm. We hypothesized that the functional starvation induced by inhibition of PFKFB3 in tumor cells might induce autophagy as a pro-survival mechanism and that the combination of drugs targeting PFKFB3 with pharmacologic inhibitors of autophagy could increase anti-tumor effects. This hypothesis has been tested and our data reveal that knockdown or inhibition of PFKFB3 results in autophagic induction. This induction appears to serve as a survival mechanism as evidenced by furthered cell death upon the addition of inhibitors of autophagy.
Klarer, Alden, "6-phosphofructo-2-kinase inhibition induces autophagy as a survival mechanism." (2013). Electronic Theses and Dissertations. Paper 760.