Unknown

Dataset Information

0

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 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.

SUBMITTER: Patel R 

PROVIDER: S-EPMC5887544 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

altmetric image

Publications


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 express  ...[more]

Similar Datasets

| S-EPMC6461206 | biostudies-literature
| S-EPMC10042887 | biostudies-literature
| S-EPMC3116285 | biostudies-literature
| S-EPMC3956942 | biostudies-other
| S-EPMC7202356 | biostudies-literature
| S-EPMC8818029 | biostudies-literature
| S-EPMC5243151 | biostudies-literature
| S-EPMC4031492 | biostudies-literature
| S-EPMC6677600 | biostudies-literature
| S-EPMC5045370 | biostudies-literature