Open AccessSprouty2 loss‐induced IL 6 drives castration‐resistant prostate cancer through scavenger receptor B1
Author(s) -
Patel Rachana,
Fleming Janis,
Mui Ernest,
Loveridge Carolyn,
Repiscak Peter,
Blomme Arnaud,
Harle Victoria,
Salji Mark,
Ahmad Imran,
Teo Katy,
Hamdy Freddie C,
Hedley Ann,
van den Broek Niels,
Mackay Gillian,
Edwards Joanne,
Sansom Owen J,
Leung Hing Y
Publication year - 2018
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201708347
Subject(s) - cancer , library science , prostate cancer , medicine , computer science
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 ( SPRY 2) is associated with treatment resistance. Using pre‐clinical human and murine mCRPC models, we show that SPRY 2 deficiency leads to an androgen self‐sufficient form of CRPC . Mechanistically, HER 2‐ IL 6 signalling axis enhances the expression of androgen biosynthetic enzyme HSD 3B1 and increases SRB 1‐mediated cholesterol uptake in SPRY 2‐deficient tumours. Systemically, IL 6 elevated the levels of circulating cholesterol by inducing host adipose lipolysis and hepatic cholesterol biosynthesis. SPRY 2‐deficient CRPC is dependent on cholesterol bioavailability and SRB 1‐mediated tumoral cholesterol uptake for androgen biosynthesis. Importantly, treatment with ITX 5061, a clinically safe SRB 1 antagonist, decreased treatment resistance. Our results indicate that cholesterol transport blockade may be effective against SPRY 2‐deficient CRPC.