Abstract LB-B07: Photoreceptor phosphodiesterase 6H expression regulates HCT116 proliferation and cell cycle progression

Abstract

Abstract Phosphodiesterase 6 (PDE6) protein complex, which is responsible for the turnover of the second messenger cyclic guanosine monophosphate (cGMP) and is involved in visual signal transduction of light stimuli, is highly expressed in certain cancer cell lines. Despite having been discovered in the outer segment of rods and cones of the retina, PDE6 protein is also detected in brain, adrenal glands, lungs, and gonads. Genes encoding the catalytic subunits of the enzyme are known to be upregulated in certain breast, non-small cell lung cancer and medulloblastoma cells. PDE6H, which encodes the cone-specific inhibitory gamma subunit of PDE6 protein, is part of the gene signature of achromatopsia and congenital stationary night blindness while its relation to cancer remains unclear. We recently identified PDE6H as a cell cycle controller in HCT116 colorectal cancer cell line, as part of an siRNA screen in which DNA content measurement via flow cytometry was undertaken to monitor cell cycle distribution. The screen was conducted with a custom library of metabolic genes commonly amplified in primary tumours, as well as those known to be involved in the key regulatory points of metabolic pathways. We have shown that PDE6H knockdown and pharmacological inhibition of PDE6 protein hindered the activity of the protein complex, causing an accumulation of cGMP in various colorectal and breast cancer cell lines. This inhibition resulted in a G1 cell cycle arrest and disruption of G1/S checkpoint mechanism. PDE6H knockdown inhibited cell proliferation and cellular oxidative phosphorylation. It also altered mitochondrial morphology and induced apoptosis. Our results suggest that the gamma subunit is important for the function of photoreceptor phosphodiesterase PDE6 complex and PDE6H inhibition can be explored as an anti-proliferative strategy. Citation Format: Ceren Yalaz, Syed Haider, Jianzhou Chen, Remko Prevo, Mick Woodcock, Adrian L. Harris, Ruth J. Muschel. Photoreceptor phosphodiesterase 6H expression regulates HCT116 proliferation and cell cycle progression [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr LB-B07.