The PI3K regulatory subunit gene PIK3R1 is under direct control of androgens and repressed in prostate cancer cells

Munkley, J. et al. (2015) The PI3K regulatory subunit gene PIK3R1 is under direct control of androgens and repressed in prostate cancer cells. Oncoscience, 2(9), pp. 755-764. (doi: 10.18632/oncoscience.243) (PMID:26501081) (PMCID:PMC4606009)

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.

• Item Type: Articles
• Additional Information: This work was funded by Prostate Cancer UK, the J. G. W Patterson Foundation, Cancer Research UK (C9380/A15574) and the Wellcome Trust (grant numbers WT080368MA and WT089225/Z/09/Z) and BBSRC (grant BB/1006923/1).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Leung, Professor Hing
• Authors: Munkley, J., Livermore, K. E., McClurg, U. L., Kalna, G., Knight, B., McCullagh, P., McGrath, J., Crundwell, M., Leung, H. Y., Robson, C. N., Harries, L. W., Rajan, P., and Elliott, D. J.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Oncoscience
• Publisher: Impact Journals
• ISSN: 2331-4737
• ISSN (Online): 2331-4737
• Copyright Holders: Copyright © 2015 The Authors
• First Published: First published in Oncoscience 2(9):755-764
• Publisher Policy: Reproduced under a Creative Commons License