Androgen receptor (AR) signalling and the PI3K pathway mediate survival signals in prostate cancer, and have been shown to regulate each other by reciprocal negative feedback, such that inhibition of one activates the other.
Understanding the reciprocal regulation of these pathways is important for disease management as tumour cells can adapt and survive when either single pathway is inhibited pharmacologically. We recently carried out genome-wide exon-specific profiling of prostate cancer cells to identify novel androgen-regulated transcriptional events. Here we interrogated this dataset for novel androgen-regulated genes associated with the PI3K pathway. We find that the PI3K regulatory subunits PIK3R1 (p85α) and PIK3R3 (p55γ) are direct targets of the AR which are rapidly repressed by androgens in LNCaP cells. Further characterisation revealed that the PIK3CA p110α catalytic subunit is also indirectly regulated by androgens at the protein level. We show that PIK3R1 mRNA is significantly under-expressed in prostate cancer (PCa) tissue, and provide data to suggest a context-dependent regulatory mechanism whereby repression of the p85α protein by the AR results in destabilisation of the PI3K p110α catalytic subunit and downstream PI3K pathway inhibition that functionally affects the properties of prostate cancer cells.
Oncoscience. 2015 Sep 14*** epublish ***
Jennifer Munkley, Karen E Livermore, Urszula L McClurg, Gabriela Kalna, Bridget Knight, Paul McCullagh, John McGrath, Malcolm Crundwell, Hing Y Leung, Craig N Robson, Lorna W Harries, Prabhakar Rajan, David J Elliott
Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, UK. , Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, UK. , Northern Institute for Cancer Research, Newcastle University, Newcastle-upon-Tyne, UK. , Cancer Research UK Beatson Institute, Glasgow, UK ; Institute of Cancer Sciences, University of Glasgow, Glasgow, UK. , NIHR Exeter Clinical Research Facility, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK. , Department of Pathology, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK. , Exeter Surgical Health Services Research Unit, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK. , Department of Urology, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK. , Cancer Research UK Beatson Institute, Glasgow, UK ; Institute of Cancer Sciences, University of Glasgow, Glasgow, UK. , Northern Institute for Cancer Research, Newcastle University, Newcastle-upon-Tyne, UK. , Institute of Biomedical and Clinical Sciences, University of Exeter, Devon, UK. , Cancer Research UK Beatson Institute, Glasgow, UK ; Institute of Cancer Sciences, University of Glasgow, Glasgow, UK. , Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, UK.