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

• Published in: International journal of molecular sciences Vol. 24; no. 6; p. 5082
• Main Authors: Duprat, Felix, Robles, Catalina, Castillo, María Paz, Rivas, Yerko, Mondaca, Marcela, Jara, Nery, Roa, Francisco, Bertinat, Romina, Toledo, Jorge, Paz, Cristian, González-Chavarría, Iván
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.03.2023; MDPI
• Subjects: Androgen Receptor Antagonists - pharmacology; Androgen receptors; Androgens; Angiogenesis; Antineoplastic Agents - pharmacology; Arteriosclerosis; Atherosclerosis; Castration; castration-resistant prostate cancer; Cell Line, Tumor; Cell proliferation; Cytokines; Cytotoxicity; Drug resistance; enzalutamide; Humans; Hypertension; Inflammation; Interleukin 6; Interleukin-6 - genetics; Interleukin-6 - pharmacology; Lipoproteins; Lipoproteins, LDL - pharmacology; Liquid oxygen; Low density lipoproteins; LOX-1; LOX-1 protein; Male; NF-kappa B - metabolism; NF-κB protein; Nitriles - pharmacology; oxLDL; Phosphorylation; Prostate cancer; Prostatic Neoplasms, Castration-Resistant - drug therapy; Prostatic Neoplasms, Castration-Resistant - genetics; Prostatic Neoplasms, Castration-Resistant - metabolism; Reactive Oxygen Species - pharmacology; Receptor density; Receptors, Androgen - metabolism; Scavenger Receptors, Class E - genetics; Scavenger Receptors, Class E - metabolism; Signal Transduction; Splicing; Stat3 protein; oxLDL; prostate cancer; castration-resistant prostate cancer; LOX-1; enzalutamide
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms24065082

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.