Cross-Resistance to Abiraterone and Enzalutamide in Castration Resistance Prostate Cancer Cellular Models Is Mediated by AR Transcriptional Reactivation
Metadatos
Mostrar el registro completo del ítemAutor
Simon, Iris; Perales Romero, Sonia; Casado Medina, Laura; Rodríguez Martínez, Alba; Garrido Navas, María del Carmen; Puche Sanz, Ignacio; Díaz Mochón, Juan José; Lorente Acosta, José Antonio; Lupiañez, Pablo; Serrano, María José; Real, Pedro J.Editorial
MDPI
Materia
Castration resistant prostate cancer Androgen receptor AR-V7 AR-V9 Transcriptional regulation Novel hormonal agents Abiraterone Enzalutamide Cross-resistance
Fecha
2021Referencia bibliográfica
Simon, I.; Perales, S.; Casado-Medina, L.; Rodríguez-Martínez, A.; Garrido-Navas, M.d.C.; Puche-Sanz, I.; Diaz-Mochon, J.J.; Alaminos, C.; Lupiañez, P.; Lorente, J.A.; et al. Cross-Resistance to Abiraterone and Enzalutamide in Castration Resistance Prostate Cancer Cellular Models Is Mediated by AR Transcriptional Reactivation. Cancers 2021, 13, 1483. https://doi.org/ 10.3390/cancers13061483
Patrocinador
Instituto de Salud Carlos III PI17/00989; European Regional Development Fund "A way to build Europe"; Ramon y Cajal - Ministry of Economy and Competitiveness RYC-2015-18382; Ministry of Education, Culture and Sport FPU14/05461; University of GranadaResumen
Androgen deprivation therapy (ADT) and novel hormonal agents (NHAs) (Abiraterone
and Enzalutamide) are the goal standard for metastatic prostate cancer (PCa) treatment. Although
ADT is initially effective, a subsequent castration resistance status (CRPC) is commonly developed.
The expression of androgen receptor (AR) alternative splicing isoforms (AR-V7 and AR-V9) has
been associated to CRPC. However, resistance mechanisms to novel NHAs are not yet well understood. Androgen-dependent PCa cell lines were used to generate resistant models to ADT only
or in combination with Abiraterone and/or Enzalutamide (concomitant models). Functional and
genetic analyses were performed for each resistance model by real-time cell monitoring assays,
flow cytometry and RT-qPCR. In androgen-dependent PCa cells, the administration of Abiraterone
and/or Enzalutamide as first-line treatment involved a critical inhibition of AR activity associated
with a significant cell growth inhibition. Genetic analyses on ADT-resistant PCa cell lines showed
that the CRPC phenotype was accompanied by overexpression of AR full-length and AR target
genes, but not necessarily AR-V7 and/or AR-V9 isoforms. These ADT resistant cell lines showed
higher proliferation rates, migration and invasion abilities. Importantly, ADT resistance induced
cross-resistance to Abiraterone and/or Enzalutamide. Similarly, concomitant models possessed an
elevated expression of AR full-length and proliferation rates and acquired cross-resistance to its
alternative NHA as second-line treatment.