Cone photoreceptor phosphodiesterase PDE6H inhibition regulates cancer cell growth and metabolism, replicating the dark retina response

• DOI: 10.1186/s40170-023-00326-y
• Publication Date: 2024-02-13T08:01:56Z
• Authors: Ceren Yalaz; Esther Bridges; Nasullah K. Alham; Christos E. Zois; Jianzhou Chen; Karim Bensaad; Ana Miar; Elisabete Pires; Ruth J. Muschel; James S. O. McCul...; Adrian L. Harris
• Keywords: Photoreceptor cell

Abstract Background PDE6H encodes PDE6γ′, the inhibitory subunit of cGMP-specific phosphodiesterase 6 in cone photoreceptors. Inhibition PDE6, which has been widely studied for its role light transduction, increases cGMP levels. The purpose this study is to characterise cancer cell growth. Methods From an siRNA screen 487 genes involved metabolism, was identified as a controller cycle progression HCT116 cells. Role growth and metabolism through effects depletion on levels controllers, mTOR effectors, metabolite levels, metabolic energy assays. Effect deletion tumour also xenograft model. Results knockout resulted increase intracellular well changes nucleotides key intermediates. knockdown induced G1 arrest death reduced mTORC1 signalling lines. Both suppression mitochondrial function. xenografts revealed that deletion, treatment with PDE5/6 inhibitor sildenafil, slowed down improved survival, while sildenafil did not have additive effect slowing PDE6γ′-deficient tumours. Conclusions Our results indicate purine pools, function observed upon PDE6γ′ depletion, are independent PKG pathway. We show HCT116, replicates many dark retina response identify new target preventing proliferation