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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 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.

Original publication

DOI

10.15252/emmm.201708347

Type

Journal article

Journal

EMBO Mol Med

Publication Date

04/2018

Volume

10

Keywords

androgen receptor, cholesterol, interleukin 6, prostate cancer, scavenger receptor B1, Animals, Humans, Interleukin-6, Intracellular Signaling Peptides and Proteins, Male, Membrane Proteins, Mice, Nude, Phenylenediamines, Prostatic Neoplasms, Castration-Resistant, Real-Time Polymerase Chain Reaction, Receptor, ErbB-2, Receptors, Scavenger, Scavenger Receptors, Class B, Signal Transduction, Sulfonamides