Sprouty2 loss‐induced IL6 drives castration‐resistant prostate cancer through scavenger receptor B1

Patel, R. et al. (2018) Sprouty2 loss‐induced IL6 drives castration‐resistant prostate cancer through scavenger receptor B1. EMBO Molecular Medicine, 10(4), e8347. (doi:10.15252/emmm.201708347) (PMID:29540470)

Patel, R. et al. (2018) Sprouty2 loss‐induced IL6 drives castration‐resistant prostate cancer through scavenger receptor B1. EMBO Molecular Medicine, 10(4), e8347. (doi:10.15252/emmm.201708347) (PMID:29540470)

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Abstract

Metastatic castration‐resistant prostate cancer (mCRPC) is a lethal form of treatment‐resistant prostate cancer and poses significant therapeutic challenges. Deregulated receptor tyrosine kinase (RTK) signalling mediated by loss of tumour suppressor Sprouty2 (SPRY2) is associated with treatment resistance. Using pre‐clinical human and murine mCRPC models, we show that SPRY2 deficiency leads to an androgen self‐sufficient form of CRPC. Mechanistically, HER2‐IL6 signalling axis enhances the expression of androgen biosynthetic enzyme HSD3B1 and increases SRB1‐mediated cholesterol uptake in SPRY2‐deficient tumours. Systemically, IL6 elevated the levels of circulating cholesterol by inducing host adipose lipolysis and hepatic cholesterol biosynthesis. SPRY2‐deficient CRPC is dependent on cholesterol bioavailability and SRB1‐mediated tumoral cholesterol uptake for androgen biosynthesis. Importantly, treatment with ITX5061, a clinically safe SRB1 antagonist, decreased treatment resistance. Our results indicate that cholesterol transport blockade may be effective against SPRY2‐deficient CRPC.

Item Type:Articles
Additional Information:This work was funded by Cancer Research UK (grant numbers A15151, A10419 and A17196) and Prostate Cancer UK (grant number PG10-10).
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Ahmad, Dr Imran and Harle, Dr Victoria and Leung, Professor Hing and Repiscak, Dr Peter and Loveridge, Ms Carolyn and Van Den Broek, Mr Niels and Mui, Mr Ernest and Salji, Dr Mark and Edwards, Professor Joanne and Mackay, Dr Gillian and Patel, Dr Rachana and Sansom, Professor Owen
Authors: Patel, R., Fleming, J., Mui, E., Loveridge, C., Repiscak, P., Blomme, A., Harle, V., Salji, M., Ahmad, I., Teo, K., Hamdy, F. C., Hedley, A., van den Broek, N., Mackay, G., Edwards, J., Sansom, O. J., and Leung, H. Y.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:EMBO Molecular Medicine
Publisher:EMBO Press
ISSN:1757-4676
ISSN (Online):1757-4684
Published Online:14 March 2018
Copyright Holders:Copyright © 2018 The Authors
First Published:First published in EMBO Molecular Medicine 10(4):e8347
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
565981Synergistic interaction between Sprouty2 loss and PI3K/AKT activation in prostate carcinogenesisHing LeungProstate Cancer UK (PROSCANU)PG10-10RI CANCER SCIENCES