Adaptive phenotype drives resistance to androgen deprivation therapy in prostate cancer

Cell Communication and Signaling

Research

Paola Barboro¹  Cecilia Balbi¹  Matteo Capaia¹  Francesco Boccardo²  Elvira Inglese³  Andrea Petretto³  Simonetta Astigiano⁴  Mario Rosario Guarracino⁵  Marina Piccirillo⁵  Ilaria Granata⁵  Martina Morini⁶  Roberta Venè⁷  Nicoletta Ferrari⁷  Antonella Brizzolara⁷  Adriana Agnese Amaro⁸ 

[1] Academic Unit of Medical Oncology, Ospedale Policlinico San Martino, L.go R. Benzi 10, 16132, Genoa, Italy;Academic Unit of Medical Oncology, Ospedale Policlinico San Martino, L.go R. Benzi 10, 16132, Genoa, Italy;Department of Internal Medicine and Medical Specialties, School of Medicine, University of Genova, L.go R. Benzi 10, 16132, Genoa, Italy;Core Facilities-Proteomics Laboratory, Giannina Gaslini Institute, L.go G. Gaslini 5, 16147, Genoa, Italy;Immunology, Ospedale Policlinico San Martino, L.go R. Benzi 10, 16132, Genoa, Italy;Institute for High Performance Computing and Networking (ICAR), National Research Council (CNR), Via Pietro Castellino 111, 80131, Naples, Italy;Laboratory of Molecular Biology, Giannina Gaslini Institute, L.go G. Gaslini 5, 16147, Genoa, Italy;Molecular Oncology and Angiogenesis, Ospedale Policlinico San Martino, L.go R. Benzi 10, 16132, Genoa, Italy;Molecular Pathology, Ospedale Policlinico San Martino, L.go R. Benzi 10, 16132, Genoa, Italy;

关键词: Castration-resistant prostate cancer;    Androgen deprivation therapy;    Drug resistance;    Stress response;    Target therapy;    Bioinformatic analysis;   

DOI  :  10.1186/s12964-017-0206-x

 received in 2017-09-13, accepted in 2017-11-28,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundProstate cancer (PCa), the second most common cancer affecting men worldwide, shows a broad spectrum of biological and clinical behaviour representing the epiphenomenon of an extreme heterogeneity. Androgen deprivation therapy is the mainstay of treatment for advanced forms but after few years the majority of patients progress to castration-resistant prostate cancer (CRPC), a lethal form that poses considerable therapeutic challenges.MethodsWestern blotting, immunocytochemistry, invasion and reporter assays, and in vivo studies were performed to characterize androgen resistant sublines phenotype in comparison to the parental cell line LNCaP. RNA microarray, mass spectrometry, integrative transcriptomic and proteomic differential analysis coupled with GeneOntology and multivariate analyses were applied to identify deregulated genes and proteins involved in CRPC evolution.ResultsTreating the androgen-responsive LNCaP cell line for over a year with 10 μM bicalutamide both in the presence and absence of 0.1 nM 5-α-dihydrotestosterone (DHT) we obtained two cell sublines, designated PDB and MDB respectively, presenting several analogies with CRPC. Molecular and functional analyses of PDB and MDB, compared to the parental cell line, showed that both resistant cell lines were PSA low/negative with comparable levels of nuclear androgen receptor devoid of activity due to altered phosphorylation; cell growth and survival were dependent on AKT and p38MAPK activation and PARP-1 overexpression; their malignant phenotype increased both in vitro and in vivo. Performing bioinformatic analyses we highlighted biological processes related to environmental and stress adaptation supporting cell survival and growth. We identified 15 proteins that could direct androgen-resistance acquisition. Eleven out of these 15 proteins were closely related to biological processes involved in PCa progression.ConclusionsOur models suggest that environmental factors and epigenetic modulation can activate processes of phenotypic adaptation driving drug-resistance. The identified key proteins of these adaptive phenotypes could be eligible targets for innovative therapies as well as molecules of prognostic and predictive value.

【 授权许可】

CC BY   
© The Author(s). 2017