Discipline: Biological Sciences
Subcategory: Cancer Research
Kevin Blake Chancellor - University of Tulsa
Co-Author(s): Robert Sheaff, University of Tulsa, Tulsa, OK
A primary but difficult goal of cancer research is to preferentially destroy tumors without harming normal cells. P27kip1 (p27) is a tumor suppressor protein commonly deregulated in aggressive cancers, and thus represents a potential target for therapeutic intervention. Current models posit that p27 disruption leads to inappropriate cell cycle progression and hyperproliferation of cancer cells. Thus, therapeutic intervention is geared towards the use of cell cycle inhibitors. However, our lab recently discovered that p27 deregulation provides cancer cells with a growth advantage by altering nutrient metabolic pathways. Thus, metabolic pathway inhibitors might be more useful for targeting cancer cells with deregulated p27. The role for p27 in cell metabolism was identified by comparing nutrient use over time in cells with and without p27. As expected, wild type cells containing p27 were completely dependent on glucose and grew until it was depleted. Cells lacking p27 also initially used glucose, but when its levels dropped modestly they abruptly switched to the amino acid glutamine. We hypothesize p27 deregulation leads to aggressive cancers because it optimizes nutrient use to promote tumor progression. During early tumorigenesis (before blood vessel formation), deregulating p27 allows use of amino acids as nutrients. As the tumor grows and develops blood vessels, p27 function is re-established to utilize plentiful glucose. We propose to exploit this metabolic switch to specifically target tumors with deregulated p27. The idea is to artificially decrease glucose levels modestly using a well-known inhibitor of glycolysis, 2-deoxy-D-glucose (2-DG). This should preferentially force the cancer cells with deregulated p27 to switch to amino acids as nutrients, at which point these metabolic pathways can be specifically targeted using drugs such as metformin and GI968. Normal cells should continue using glucose, meaning they will not be affected by drug treatment. Preliminary results indicate that cells lacking p27 can be preferentially killed without affecting viability of normal cells, supporting further development of this drug treatment protocol for targeting aggressive cancers with deregulated p27.
Funder Acknowledgement(s): University of Tulsa Donors/University of Tulsa Internal Funding.
Faculty Advisor: Robert Sheaff,