1. Cross-Resistance to Abiraterone and Enzalutamide in Castration Resistance Prostate Cancer Cellular Models Is Mediated by AR Transcriptional Reactivation
- Author
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Ignacio Puche-Sanz, Pedro J. Real, Pablo Lupiañez, Sonia Perales, Iris Simon, Clara Alaminos, José A. Lorente, Alba Rodríguez-Martínez, Laura Casado-Medina, Juan J. Díaz-Mochón, María José Serrano, María del Carmen Garrido-Navas, [Simon,I, Perales,S, Casado-Medina,L, Lupiañez,P, Real,PJ] GENyO, Centre for Genomics and Oncological Research, Pfizer-University of Granada-Andalusian Regional Government, Gene Regulation, Stem Cells & Development Lab, PTS Granada, Granada, Spain. [Simon,I, Real,PJ] Faculty of Science, Department of Biochemistry and Molecular Biology I, University of Granada, Granada, Spain. [Rodríguez-Martínez,A, Garrido-Navas,MDC, Lorente,JA, Serrano,MJ] GENyO, Centre for Genomics and Oncological Research, Pfizer-University of Granada-Andalusian Regional Government, Liquid Biopsy and Cancer Interception Group, PTS Granada, Granada, Spain. [Rodríguez-Martínez,A, Lorente,JA] Faculty of Medicine, Legal Medicine and Toxicology Department, University of Granada, Laboratory of Genetic Identification, Spain. [Garrido-Navas,MDC] Universidad Internacional de la Rioja, Logroño, Spain. [Puche-Sanz,I] Department of Urology, Bio-Health Research Institute (Instituto de Investigación Biosanitaria ibs.GRANADA), Hospital Universitario Virgen de las Nieves, University of Granada, Granada, Spain. [Diaz-Mochon, JJ] GENyO, Centre for Genomics and Oncological Research, Pfizer-University of Granada-Andalusian Regional Government, Nanochembio Lab, PTS Granada, Granada, Spain. [Diaz-Mochon,JJ] Department of Pharmaceutical and Organic Chemistry, Faculty of Pharmacy, Campus de Cartuja, University of Granada, Granada, Spain. [Alaminos,C] Department of Urology, University Hospital of Jaen, Jaen, Spain. [Serrano,MJ] Comprehensive Oncology Division, Clinical University Hospital, Virgen de las Nieves-IBS, Granada, Spain. [Serrano,MJ] Department of Pathological Anatomy, Faculty of Medicine, University of Granada, Granada, Spain. [Real, PJ] Bio-Health Research Institute (Instituto de Investigación Biosanitaria ibs.GRANADA), Personalized Oncology Group, Granada, Spain, This study was supported by the Institute of Health Carlos III, Spain (PI17/00989) to M.J.S. and cofunded by the European Regional Development Fund 'A way to build Europe' and the Ramon y Cajal (RYC-2015-18382) to P.J.R., funded by the Ministry of Economy and Competitiveness. A.R.-M. was supported by the predoctoral-University Teacher Training Program from the Ministry of Education, Culture and Sport (FPU14/05461), I.S. was supported by the Young Researcher program from University of Granada (Joven Personal Investigador-Fondo Social Europeo, and Universidad de Granada (2018-19)) and a donation from Rolucan Association (Rota Lucha contra el Cancer).
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0301 basic medicine ,Cancer Research ,Phenomena and Processes::Genetic Phenomena::Phenotype [Medical Subject Headings] ,castration resistant prostate cancer ,Cell ,Andrógenos ,urologic and male genital diseases ,Diseases::Male Urogenital Diseases::Urogenital Neoplasms::Genital Neoplasms, Male::Prostatic Neoplasms::Prostatic Neoplasms, Castration-Resistant [Medical Subject Headings] ,Androgen deprivation therapy ,chemistry.chemical_compound ,Prostate cancer ,0302 clinical medicine ,Castration Resistance ,Anatomy::Cells::Cells, Cultured::Cell Line [Medical Subject Headings] ,androgen receptor ,abiraterone ,transcriptional regulation ,Abiraterone ,Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Diagnostic Techniques and Procedures::Clinical Laboratory Techniques::Cytological Techniques::Cytophotometry::Flow Cytometry [Medical Subject Headings] ,medicine.diagnostic_test ,Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Protein Isoforms [Medical Subject Headings] ,enzalutamide ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Androgen receptor ,medicine.anatomical_structure ,Elementos reguladores de la transcripción ,Oncology ,Chemicals and Drugs::Hormones, Hormone Substitutes, and Hormone Antagonists::Hormone Antagonists::Androgen Antagonists [Medical Subject Headings] ,030220 oncology & carcinogenesis ,Castration resistant prostate cancer ,cross-resistance ,Check Tags::Male [Medical Subject Headings] ,lcsh:RC254-282 ,Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression Regulation::RNA Processing, Post-Transcriptional::RNA Splicing::Alternative Splicing [Medical Subject Headings] ,Article ,Flow cytometry ,03 medical and health sciences ,Transcriptional regulation ,Psychiatry and Psychology::Behavior and Behavior Mechanisms::Motivation::Goals [Medical Subject Headings] ,Acetato de abiraterona ,medicine ,Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Physiological Effects of Drugs::Hormones, Hormone Substitutes, and Hormone Antagonists::Hormones::Androgens [Medical Subject Headings] ,Enzalutamide ,Cross-resistance ,Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Growth Processes::Cell Proliferation [Medical Subject Headings] ,Cell growth ,business.industry ,Analytical, Diagnostic and Therapeutic Techniques and Equipment::Surgical Procedures, Operative::Urogenital Surgical Procedures::Castration [Medical Subject Headings] ,Neoplasias de la próstata resistentes a la castración ,medicine.disease ,030104 developmental biology ,chemistry ,Novel hormonal agents ,Cancer research ,Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Receptors, Cytoplasmic and Nuclear::Receptors, Steroid::Receptors, Androgen [Medical Subject Headings] ,business ,AR-V7 ,AR-V9 - Abstract
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., 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 Granada
- Published
- 2021