Sprouty2 loss‐induced IL6 drives castration‐resistant prostate cancer through scavenger receptor B1
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 treat...
Main Authors: | , , , , , , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Wiley
2018-04-01
|
Series: | EMBO Molecular Medicine |
Subjects: | |
Online Access: | https://doi.org/10.15252/emmm.201708347 |
id |
doaj-f68a51d6e42349948384f58cf1f57479 |
---|---|
record_format |
Article |
spelling |
doaj-f68a51d6e42349948384f58cf1f574792021-08-02T18:40:42ZengWileyEMBO Molecular Medicine1757-46761757-46842018-04-01104n/an/a10.15252/emmm.201708347Sprouty2 loss‐induced IL6 drives castration‐resistant prostate cancer through scavenger receptor B1Rachana Patel0Janis Fleming1Ernest Mui2Carolyn Loveridge3Peter Repiscak4Arnaud Blomme5Victoria Harle6Mark Salji7Imran Ahmad8Katy Teo9Freddie C Hamdy10Ann Hedley11Niels van den Broek12Gillian Mackay13Joanne Edwards14Owen J Sansom15Hing Y Leung16Cancer Research UK Beatson Institute Glasgow UKCancer Research UK Beatson Institute Glasgow UKInstitute of Cancer Sciences Glasgow UKInstitute of Cancer Sciences Glasgow UKInstitute of Cancer Sciences Glasgow UKCancer Research UK Beatson Institute Glasgow UKInstitute of Cancer Sciences Glasgow UKInstitute of Cancer Sciences Glasgow UKCancer Research UK Beatson Institute Glasgow UKInstitute of Cancer Sciences Glasgow UKNuffield Department of Surgical Sciences John Radcliffe Hospital University of Oxford Headington, Oxford UKCancer Research UK Beatson Institute Glasgow UKCancer Research UK Beatson Institute Glasgow UKCancer Research UK Beatson Institute Glasgow UKInstitute of Cancer Sciences Glasgow UKCancer Research UK Beatson Institute Glasgow UKCancer Research UK Beatson Institute Glasgow UKAbstract 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.https://doi.org/10.15252/emmm.201708347androgen receptorcholesterolinterleukin 6prostate cancerscavenger receptor B1 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
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 |
spellingShingle |
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 androgen receptor cholesterol interleukin 6 prostate cancer scavenger receptor B1 |
author_facet |
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 |
author_sort |
Rachana Patel |
title |
Sprouty2 loss‐induced IL6 drives castration‐resistant prostate cancer through scavenger receptor B1 |
title_short |
Sprouty2 loss‐induced IL6 drives castration‐resistant prostate cancer through scavenger receptor B1 |
title_full |
Sprouty2 loss‐induced IL6 drives castration‐resistant prostate cancer through scavenger receptor B1 |
title_fullStr |
Sprouty2 loss‐induced IL6 drives castration‐resistant prostate cancer through scavenger receptor B1 |
title_full_unstemmed |
Sprouty2 loss‐induced IL6 drives castration‐resistant prostate cancer through scavenger receptor B1 |
title_sort |
sprouty2 loss‐induced il6 drives castration‐resistant prostate cancer through scavenger receptor b1 |
publisher |
Wiley |
series |
EMBO Molecular Medicine |
issn |
1757-4676 1757-4684 |
publishDate |
2018-04-01 |
description |
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. |
topic |
androgen receptor cholesterol interleukin 6 prostate cancer scavenger receptor B1 |
url |
https://doi.org/10.15252/emmm.201708347 |
work_keys_str_mv |
AT rachanapatel sprouty2lossinducedil6drivescastrationresistantprostatecancerthroughscavengerreceptorb1 AT janisfleming sprouty2lossinducedil6drivescastrationresistantprostatecancerthroughscavengerreceptorb1 AT ernestmui sprouty2lossinducedil6drivescastrationresistantprostatecancerthroughscavengerreceptorb1 AT carolynloveridge sprouty2lossinducedil6drivescastrationresistantprostatecancerthroughscavengerreceptorb1 AT peterrepiscak sprouty2lossinducedil6drivescastrationresistantprostatecancerthroughscavengerreceptorb1 AT arnaudblomme sprouty2lossinducedil6drivescastrationresistantprostatecancerthroughscavengerreceptorb1 AT victoriaharle sprouty2lossinducedil6drivescastrationresistantprostatecancerthroughscavengerreceptorb1 AT marksalji sprouty2lossinducedil6drivescastrationresistantprostatecancerthroughscavengerreceptorb1 AT imranahmad sprouty2lossinducedil6drivescastrationresistantprostatecancerthroughscavengerreceptorb1 AT katyteo sprouty2lossinducedil6drivescastrationresistantprostatecancerthroughscavengerreceptorb1 AT freddiechamdy sprouty2lossinducedil6drivescastrationresistantprostatecancerthroughscavengerreceptorb1 AT annhedley sprouty2lossinducedil6drivescastrationresistantprostatecancerthroughscavengerreceptorb1 AT nielsvandenbroek sprouty2lossinducedil6drivescastrationresistantprostatecancerthroughscavengerreceptorb1 AT gillianmackay sprouty2lossinducedil6drivescastrationresistantprostatecancerthroughscavengerreceptorb1 AT joanneedwards sprouty2lossinducedil6drivescastrationresistantprostatecancerthroughscavengerreceptorb1 AT owenjsansom sprouty2lossinducedil6drivescastrationresistantprostatecancerthroughscavengerreceptorb1 AT hingyleung sprouty2lossinducedil6drivescastrationresistantprostatecancerthroughscavengerreceptorb1 |
_version_ |
1721228023969087488 |