Upregulation of Scavenger Receptor B1 Is Required for Steroidogenic and Nonsteroidogenic Cholesterol Metabolism in Prostate Cancer

Abstract

Aberrant cholesterol metabolism is increasingly appreciated to be essential for prostate cancer (PCa) initiation and progression. Transcript expression of the high-density lipoprotein-cholesterol receptor scavenger receptor B1 (SR-B1) is elevated in primary PCa. Hypothesizing that SR-B1 expression may help facilitate malignant transformation, we document increased SR-B1 protein and transcript expression in PCa relative to normal prostate epithelium that persists in lethal castration-resistant prostate cancer (CRPC) metastasis. As intratumoral steroid synthesis from the precursor cholesterol can drive androgen receptor (AR) pathway activity in CRPC, we screened androgenic benign and cancer cell lines for sensitivity to SR-B1 antagonism. Benign cells were insensitive to SR-B1 antagonism, and cancer line sensitivity inversely correlated with expression levels of full-length and splice-variant AR. In androgen-responsive CRPC cell model C4-2, SR-B1 antagonism suppressed cholesterol uptake, de novo steroidogenesis, and AR activity. SR-B1 antagonism also suppressed growth and viability and induced endoplasmic reticulum stress and autophagy. The inability of exogenous steroids to reverse these effects indicates that AR pathway activation is insufficient to overcome cytotoxic stress caused by a decrease in the availability of cholesterol. Furthermore, SR-B1 antagonism decreased cholesterol uptake, growth, and viability of the AR-null CRPC cell model PC-3, and the small molecule SR-BI antagonist Block Lipid Transport-1 decreased xenograft growth rate despite poor pharmacologic properties. Overall, our findings show that SR-B1 is upregulated in primary and castration-resistant disease and is essential for cholesterol uptake needed to drive both steroidogenic and non-steroidogenic biogenic pathways, thus implicating SR-B1 as a novel and potentially actionable target in CRPC.

SR-B1 uptake of HDL promotes prostate cancer proliferation and tumor progression

“…Gordon et al also reported increased SR-B1 mRNA expression, but lower LDLR mRNA expression, in prostate cancer vs. matched normal prostatic tissue (23). Our TCGA data analysis showed that SR-B1 mRNA is upregulated and that ABCA1 mRNA is decreased in prostate cancer vs. paired adjacent normal tissue, in agreement with the above studies (22,23).…”

“…Furthermore, we showed that Alexa568-HDL uptake by TRAMP-C2 cells was in part mediated by SR-B1 ( Fig. 5A, B), a finding that was demonstrated by Gordon et al, in C4-2 prostate cancer cells in which DiI-HDL uptake was partially reduced upon SR-B1 knock down or chemical inhibition by BLT-1 (23). We found that inhibiting de novo cholesterol synthesis in TRAMP-C2 cells by lovastatin led to reduced cell accumulation, which was rescued by HDL treatment in an SR-B1 dependent fashion, suggesting that the cholesterol content of HDL may play a role in the recovery of cell accumulation ( Fig.…”

“…Since other studies (22,23) and our analysis of the TCGA data set showed upregulation of SR-B1 in prostate cancer ( Fig. 1), we hypothesized that HDL may drive an increase of total cholesterol levels, similarly to what was previously illustrated for LDL (16).…”

“…Furthermore it was shown that that high vs. low SR-B1 expression in prostatectomy specimens was associated with decreased progression-free survival (22). In a small study, SR-B1 mRNA levels were significantly higher in prostate cancer tissue vs. matched normal prostate tissue (23). In our study, we examined the effect of HDL on prostate cancer cell growth, proliferation, and tumor progression.…”

“…Previous studies have focused on lipoprotein receptors in prostate cancer, and how their changes may influence cholesterol transport in prostate cancer (16,(22)(23)(24).…”