Inhibition of Scavenger Receptor Class B Type 1 (SR-B1) Expression and Activity as a Potential Novel Target to Disrupt Cholesterol Availability in Castration-Resistant Prostate Cancer

Abstract

There have been several studies that have linked elevated scavenger receptor class b type 1 (SR-B1) expression and activity to the development and progression of castration-resistant prostate cancer (CRPC). SR-B1 facilitates the influx of cholesterol to the cell from lipoproteins in systemic circulation. This influx of cholesterol may be important for many cellular functions, including the synthesis of androgens. Castration-resistant prostate cancer tumors can synthesize androgens de novo to supplement the loss of exogenous sources often induced by androgen deprivation therapy. Silencing of SR-B1 may impact the ability of prostate cancer cells, particularly those of the castration-resistant state, to maintain the intracellular supply of androgens by removing a supply of cholesterol. SR-B1 expression is elevated in CRPC models and has been linked to poor survival of patients. The overarching belief has been that cholesterol modulation, through either synthesis or uptake inhibition, will impact essential signaling processes, impeding the proliferation of prostate cancer. The reduction in cellular cholesterol availability can impede prostate cancer proliferation through both decreased steroid synthesis and steroid-independent mechanisms, providing a potential therapeutic target for the treatment of prostate cancer. In this article, we discuss and highlight the work on SR-B1 as a potential novel drug target for CRPC management.

New insights into lipid metabolism and prostate cancer (Review)

“…PCa cells can regulate intracellular cholesterol levels through various pathways, such as endocytosis, exocytosis, synthesis and degradation, and certain transcription factors play a critical role in this process. SREBP-2 promotes endogenous cholesterol synthesis and increases cholesterol levels (103); SR-B1 promotes cholesterol influx from lipoproteins in the body circulation into cells (104) and is necessary to drive cholesterol uptake required for steroidal and nonsteroidal biological pathways (102), while liver X receptor promotes cholesterol efflux (60) and downregulates AKT survival signaling in lipid rafts to induce the apoptosis of PCa cells (105).…”

Emerging strategies in targeting tumor-resident myeloid cells for cancer immunotherapy

“…Given MARCO ligands primarily include acetylated-LDL and negatively charged molecules, sulfatides (negatively charged glycolipids) became one of the first low molecular weight inhibitors to spark interest [ 423 ]. While the development of inhibitors against class A scavenger receptors like MARCO remains in its infancy, inhibitors against other scavenger receptor classes such as SR-B1, SR-B2, and LOX-1 are also available for evaluation [ 424 ].…”

Polymorphism of 3β-Hydroxysteroid Dehydrogenase-1 in patients with prostate cancer in middle Euphrates of Iraq

“…Although initially most prostate cancers respond well to ADT, most patients eventually progress to castration-resistant prostate cancer (CRPC), which is mainly thought to be because androgen receptor reactivation is induced by several mechanisms (5). One of those mechanisms have been identified to be intratumoral androgen synthesis mostly from adrenal precursor steroids and at least in part due to de novo synthesis from cholesterol (6,7,8) which is supported by increased expression of several genes encoding steroidogenic enzymes such as HSD3B (9). HSD3B1 encodes 3β-hydroxysteroid dehydrogenase-1, which is mainly expressed in peripheral tissues including the prostate, breast, skin, and placenta (10).…”