Characterization of PIK3CD as a Cancer Drug Target

Abstract

Peroxisome proliferator activated Receptors (PPARs) belong to the nuclear receptor super family and are ligand activated transcription factors regulating the expression of a wide variety of genes. On activation by a ligand, they bind to the PPAR-responsive regulatory elements (PPRE) and/or PPAR associated conserved motif (PACM) as obligate heterodimers with retinoid X recep¬tor (RXR). Recently, several reports have shown a consistent link between PPARγ activation and anti-tumorigenic effects in several tumor cell lines. Although several mechanisms have been proposed for this anti-tumorigenic effect on PPARγ activation, one of the potential mechanisms is the inhibition of telomerase activity and modulation of hTERT expression through the Myc/Mad/Max genes that are downstream targets of PPARγ. This mechanism is very interesting because hTERT expression is upregulated in 90% of the cancer cells. Our lab has computationally predicted over 1100 genes that are potentially regulated by PPARγ. Several of these targets have been identified in a genome-wide screen that was driven to identify factors that selectively kill hTERT overexpressing cells. My project involves validation of these targets using metabolic, proliferation and expression assays. Finally, we validated one potential target of PPARγ that can selectively kill hTERT overexpressing cells. These investigations have applications in cancer therapeutics.