Repositorio
Institucional

Gonzalez-Chavarria, Ivan

Duprat, Felix

Robles, Catalina

Castillo, Maria Paz

Rivas, Yerko

Mondaca, Marcela

Jara, Nery

Roa, Francisco

Bertinat, Romina

Toledo, Jorge

Paz, Cristian

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

MDPI

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES

en

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-kappa B 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-kappa B 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-kappa B, 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.

2023

artículo original

10.3390/ijms24065082

PDF

prostate cancer

castration-resistant prostate cancer

oxLDL

LOX-1

enzalutamide

Bioquímica y biología molecular

Química

Cancer de prostata

cáncer de próstata resistente a la castración

LDLox

LOX-1

enzalutamida

artículo original

versión publicada

CC BY 4.0

CC BY 4.0

acceso abierto

acceso abierto

WOS:000958277600001

verde# dorado

Bioquímica y biología molecular

Química

ANID-FONDECYT 11181105

ANID-FONDECYT 11191195

ANID-FONDECYT 1201217

ANID FONDECYT 11181105

ANID FONDECYT 11191195

ANID FONDECYT 1201217