LOX-1 Activation by oxLDL Induces AR and AR-V7 Expression via NF-κB and STAT3 Signaling Pathways Reducing Enzalutamide Cytotoxic Effects

Abstract

The oxidized low-density lipoprotein receptor 1 (LOX-1) is one of the most important receptors for modified LDLs, such as oxidated (oxLDL) and acetylated (acLDL) low-density lipoprotein. LOX-1 and oxLDL are fundamental in atherosclerosis, where oxLDL/LOX1 promotes ROS generation and NF-κB activation inducing the expression of IL-6, a STAT3 activator. Furthermore, LOX-1/oxLDL function has been associated with other diseases, such as obesity, hypertension, and cancer. In prostate cancer (CaP), LOX-1 overexpression is associated with advanced stages, and its activation by oxLDL induces an epithelial-mesenchymal transition, increasing angiogenesis and proliferation. Interestingly, enzalutamide-resistant CaP cells increase the uptake of acLDL. Enzalutamide is an androgen receptor (AR) antagonist for castration-resistant prostate cancer (CRPC) treatment, and a high percentage of patients develop a resistance to this drug. The decreased cytotoxicity is promoted in part by STAT3 and NF-κB activation that induces the secretion of the pro-inflammatory program and the expression of AR and its splicing variant AR-V7. Here, we demonstrate for the first time that oxLDL/LOX-1 increases ROS levels and activates NF-κB, inducing IL-6 secretion and the activation of STAT3 in CRPC cells. Furthermore, oxLDL/LOX1 increases AR and AR-V7 expression and decreases enzalutamide cytotoxicity in CRPC. Thus, our investigation suggests that new factors associated with cardiovascular pathologies, such as LOX-1/oxLDL, may also promote important signaling axes for the progression of CRPC and its resistance to drugs used for its treatment.

The role of proinflammatory cytokines and CXC chemokines (CXCL1–CXCL16) in the progression of prostate cancer: insights on their therapeutic management

“…Recent studies show that oxLDL/LOX-1 increases reactive oxygen species (ROS), activates NF- k B, produces IL-6, and activates STAT3, enabling CRPC to be resistant to enzalutamide. These findings suggest that LOX-1/oxLDL-related new factors may enhance CRPC signaling [ 73 ]. IL-6 functions as a hub gene that may facilitate immune cell homing and differentiation in PCa [ 74 ].…”

Atherosclerosis, Diabetes Mellitus, and Cancer: Common Epidemiology, Shared Mechanisms, and Future Management

“…The majority of the atherogenic effects of oxLDL on endothelial function are regulated through the expression and activation of Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 (LOX-1) [58]. LOX-1 belongs to class E scavenger receptors (SRs) and has the ability to bind to dysfunctional lipids, like oxLDL, fundamental in atherosclerosis and other diseases, like obesity, hypertension, and cancer [238]. LOX-1 is upregulated by many inflammatory mediators and proatherogenic stimuli but has no known enzymatic or catalytic activity, and ligand binding has been shown to trigger intracellular signaling [18,239].…”

Functional Roles of CD133: More than Stemness Associated Factor Regulated by the Microenvironment

“…Interleukins produced by CD206 + macrophage cells could induce STAT signaling in tumoral cells, which upregulate CD133 and CD44 expression [ 183 ]. Further, ox-LDL could trigger ROS/NFkβ/interleukins that act in an autocrine manner to activate STAT3 and subsequent target gene expression [ 197 ]. Also, other soluble factors such as TGFβ and TNFα/β from T Regs and T cells respectively, activate NFkB/Interleukins axis to probably reinforce STAT signaling in a feedback loop [ 176 , 181 ].…”