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A Novel Communication Role For CYP17A1 In The Progression Of Castration-Resistant Prostate Cancer

July 16, 2017

UroToday - This publication describes our unique finding that the steroidogenic enzyme CYP17A1 is present in prostate derived exosomes, isolated from human serum. We also describe CYP17A1 expression in human prostate tissues during castration resistant progression of cancer and identify a subcellular pattern of distribution for CYP17A1 consistent with a secretory protein in human prostate tissues, similar to that of PSA.

Amongst the numerous proteins shown to be present in prostasomes we have found this key steroidogenic enzyme involved in testosterone synthesis from cholesterol. CYP17A1 is currently a target of investigational agents such as Abiraterone, which is under investigation for the treatment of advanced castration resistant disease. We postulate that this phenomenon is a cellular response triggered by upregulation of processes required for the cell to undergo cholesterol mediated steroid synthesis to testosterone and DHT within prostate tumour cells and is an adaptive resistance mechanism to depletion of androgens. Despite our inability to demonstrate metabolic enzyme activity in exosome isolates, we believe that CYP17A1 presence in the serum and its elevation in cancer patients compared with healthy controls suggests that it may be a novel diagnostic biomarker. Beyond its potential as a biomarker we propose that CYP17A1 could be playing a communication role in castrate resistant cancer development. In the absence of a supply of testicular androgens, when mechanisms involved in de novo androgen synthesis have been shown to be activated1, exosomal 'life-rafts' are released from the cell, loaded with 'adaptive survival messages' for other cells to host and potentially assimilate in order to enhance chances of survival. This hypothesis works on the basis that elevated cholesterol levels are observed in cancer cells during castration resistant development, which in turn has been shown to regulate an increase in the extrusion of prostate derived exosomes into the cancer microenvironment2, triggers the release of these 'exosomal 'life rafts'.

References:

1. Locke J, Guns ES, Lubik A, Adomat H, Hendy S, Wood C, Gleave ME, Nelson CC: De Novo Synthesis of Androgens as a Potential Mechanism behind Androgen-Independent Prostate Cancer Progression. Cancer Res. 2008 Aug 1;68(15):6407-15

2. Llorente A, van Deurs, B and Sandvig, K: Cholesterol regulates prostasome release from secretory lysosomes in PC-3 human prostate cancer cells. European Journal of Cell Biology 86 (2007) 405-415

Manuscript: Locke J, Fazli L, Adomat H, Smyl J, Weins K, Barr S, Lubik A, Hales B, Nelson CC, Gleave M and Tomlinson Guns ES: CYP17A1 is elevated in the serum of prostate cancer patients as compared to healthy controls. Prostate Mar 2009 [EPub ahead of print]

Emma Tomlinson Guns, PhD as part of Beyond the Abstract on UroToday

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