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) (PMCID:PMC5887544)
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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, Professor Imran and Harle, Dr Victoria and Leung, Professor Hing and Van Den Broek, Mr Niels and Salji, Dr Mark and Mui, Mr Ernest and Edwards, Professor Joanne and Repiscak, Dr Peter and Mackay, Dr Gillian and Patel, Dr Rachana and Loveridge, Dr Carolyn 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 > School 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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