Publikationsdatenbank

Upregulation of scavenger receptor B1 is required for steroidogenic and nonsteroidogenic cholesterol metabolism in prostate cancer (2019)

Art

Zeitschriftenartikel / wissenschaftlicher Beitrag

Autoren

Gordon, Jacob A.

Noble, Jake W.

Midha, Ankur (WE 6)

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.

Quelle

Cancer research

Bandzählung: 79

Heftzählung: 13

Seiten: 3320 – 3331

ISSN: 0008-5472

Sprache

Englisch

Verweise

URL (Volltext): https://cancerres.aacrjournals.org/content/79/13/3320

DOI: 10.1158/0008-5472.CAN-18-2529

Pubmed: 31064850

Kontakt

Institut für Immunologie

Robert-von-Ostertag-Str. 7-13
14163 Berlin
+49 30 838 51834
immunologie@vetmed.fu-berlin.de

Abstract / Zusammenfassung

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, 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-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.