The PI3K regulatory subunit gene PIK3R1 is under direct control of androgens and repressed in prostate cancer cells
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https://doi.org/10.18632/oncoscience.243
Jennifer Munkley1, Karen E. Livermore1, Urszula L. McClurg2, Gabriela Kalna3,4, Bridget Knight5, Paul McCullagh6, John McGrath7, Malcolm Crundwell8, Hing Y. Leung3,4, Craig N. Robson2, Lorna W. Harries9 Prabhakar Rajan3,4 and David J. Elliott1
1 Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, UK
2 Northern Institute for Cancer Research, Newcastle University, Newcastle-upon-Tyne, UK
3 Cancer Research UK Beatson Institute, Glasgow, UK
4 Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
5 NIHR Exeter Clinical Research Facility, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK
6 Department of Pathology, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK
7 Exeter Surgical Health Services Research Unit, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK
8 Department of Urology, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK
9 Institute of Biomedical and Clinical Sciences, University of Exeter, Devon, UK
Correspondence:
Jennifer Munkley, email:
Keywords: PI3K signalling, PIK3R1, p85α, androgens, prostate cancer
Received: August 18, 2015 Accepted: September 12, 2015 Published: September 14, 2015
Abstract
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 (p85ɑ) and PIK3R3 (p55ʏ) are direct targets of the AR which are rapidly repressed by androgens in LNCaP cells. Further characterisation revealed that the PIK3CA p110ɑ 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 p85ɑ protein by the AR results in destabilisation of the PI3K p110ɑ catalytic subunit and downstream PI3K pathway inhibition that functionally affects the properties of prostate cancer cells.
