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

EMBO molecular medicine 2018 Apr

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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 bios ynthesis. 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. © 2018 The Authors. Published under the terms of the CC BY 4.0 license.

Citation

Rachana Patel, Janis Fleming, Ernest Mui, Carolyn Loveridge, Peter Repiscak, Arnaud Blomme, Victoria Harle, Mark Salji, Imran Ahmad, Katy Teo, Freddie C Hamdy, Ann Hedley, Niels van den Broek, Gillian Mackay, Joanne Edwards, Owen J Sansom, Hing Y Leung. Sprouty2 loss-induced IL6 drives castration-resistant prostate cancer through scavenger receptor B1. EMBO molecular medicine. 2018 Apr;10(4)