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

Animals; Humans; Interleukin-6/metabolism; Intracellular Signaling Peptides and Proteins/genetics/metabolism; Male; Membrane Proteins/genetics/metabolism; Mice, Nude; Phenylenediamines/therapeutic use; Prostatic Neoplasms, Castration-Resistant/drug therapy/metabolism; Protein-Serine-Threonine Kinases; Real-Time Polymerase Chain Reaction; Receptor, ErbB-2/genetics/metabolism; Receptors, Scavenger/metabolism; Scavenger Receptors, Class B/antagonists & inhibitors; Signal Transduction/drug effects/physiology; Sulfonamides/therapeutic use; androgen receptor; cholesterol; interleukin 6; prostate cancer; scavenger receptor B1

Abstract :

[en] 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.

Disciplines :

Biochemistry, biophysics & molecular biology

Author, co-author :

Patel, Rachana

Fleming, Janis

Mui, Ernest

Loveridge, Carolyn

Repiscak, Peter

Blomme, Arnaud ; Université de Liège - ULiège > Stem Cells-Cancer Signaling

Harle, Victoria

Salji, Mark

Ahmad, Imran

Teo, Katy

More authors (7 more)

Language :

English

Title :

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

Publication date :

2018

Journal title :

EMBO Molecular Medicine

ISSN :

1757-4676

eISSN :

1757-4684

Publisher :

Wiley-Blackwell, United Kingdom

Volume :

Issue :

Peer reviewed :

Peer Reviewed verified by ORBi

Commentary :

Available on ORBi :

since 09 June 2020

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