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

Aberrant cholesterol metabolism is increasingly appreciated to be essential for prostate cancer initiation and progression. Transcript expression of the high-density lipoprotein-cholesterol receptor scavenger receptor B1 (SR-B1) is elevated in primary prostate cancer. Hypothesizing that SR-B1 expres...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2019-07, Vol.79 (13), p.3320-3331
Main Authors: Gordon, Jacob A, Noble, Jake W, Midha, Ankur, Derakhshan, Fatemeh, Wang, Gang, Adomat, Hans H, Tomlinson Guns, Emma S, Lin, Yen-Yi, Ren, Shancheng, Collins, Collin C, Nelson, Peter S, Morrissey, Colm, Wasan, Kishor M, Cox, Michael E
Format: Article
Language:English
Subjects:
Androgens - metabolism
Animals
Apoptosis
Biomarkers, Tumor - genetics
Biomarkers, Tumor - metabolism
Bone Neoplasms - metabolism
Bone Neoplasms - secondary
Bone Neoplasms - surgery
Cell Proliferation
Cholesterol - metabolism
Gene Expression Regulation, Neoplastic
Humans
Liver Neoplasms - metabolism
Liver Neoplasms - secondary
Liver Neoplasms - surgery
Lung Neoplasms - metabolism
Lung Neoplasms - secondary
Lung Neoplasms - surgery
Male
Mice
Mice, Nude
Orchiectomy
Prognosis
Prostatic Neoplasms, Castration-Resistant - metabolism
Prostatic Neoplasms, Castration-Resistant - pathology
Prostatic Neoplasms, Castration-Resistant - surgery
Receptors, Androgen - genetics
Receptors, Androgen - metabolism
Scavenger Receptors, Class B - genetics
Scavenger Receptors, Class B - metabolism
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
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Summary:Aberrant cholesterol metabolism is increasingly appreciated to be essential for prostate cancer initiation and progression. Transcript expression of the high-density lipoprotein-cholesterol receptor scavenger receptor B1 (SR-B1) is elevated in primary prostate cancer. Hypothesizing that SR-B1 expression may help facilitate malignant transformation, we document increased SR-B1 protein and transcript expression in prostate cancer 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, 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-B1 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 nonsteroidogenic biogenic pathways, thus implicating SR-B1 as a novel and potentially actionable target in CRPC. SIGNIFICANCE: These findings highlight SR-B1 as a potential target in primary and castration-resistant prostate cancer that is essential for cholesterol uptake needed to drive steroidogenic and nonsteroidogenic biogenic pathways.
ISSN:0008-5472
1538-7445
1538-7445
DOI:10.1158/0008-5472.can-18-2529