title: Androgen deprivation-induced senescence promotes outgrowth of androgen-refractory prostate cancer cells.
abstract: Androgen deprivation (AD) is an effective method for initially suppressing prostate cancer (PC) progression. However, androgen-refractory PC cells inevitably emerge from the androgen-responsive tumor, leading to incurable disease. Recent studies have shown AD induces cellular senescence, a phenomenon that is cell-autonomously tumor-suppressive but which confers tumor-promoting adaptations that can facilitate the advent of senescence-resistant malignant cell populations. Because androgen-refractory PC cells emerge clonally from the originally androgen-responsive tumor, we sought to investigate whether AD-induced senescence (ADIS) affects acquisition of androgen-refractory behavior in androgen-responsive LNCaP and LAPC4 prostate cancer cells. We find that repeated exposure of these androgen-responsive cells to senescence-inducing stimuli via cyclic AD leads to the rapid emergence of ADIS-resistant, androgen-refractory cells from the bulk senescent cell population. Our results show that the ADIS phenotype is associated with tumor-promoting traits, notably chemoresistance and enhanced pro-survival mechanisms such as inhibition of p53-mediated cell death, which encourage persistence of the senescent cells. We further find that pharmacologic enforcement of p53/Bax activation via Nutlin-3 prior to establishment of ADIS is required to overcome the associated pro-survival response and preferentially trigger pervasive cell death instead of senescence during AD. Thus our study demonstrates that ADIS promotes outgrowth of androgen-refractory PC cells and is consequently a suboptimal tumor-suppressor response to AD.
authors.affiliation: Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
authors.forename: Dominick G A
authors.initials: DG
authors.lastname: Burton
authors.forename: Maria G
authors.initials: MG
authors.lastname: Giribaldi
authors.forename: Anisleidys
authors.initials: A
authors.lastname: Munoz
authors.forename: Katherine
authors.initials: K
authors.lastname: Halvorsen
authors.forename: Asmita
authors.initials: A
authors.lastname: Patel
authors.forename: Merce
authors.initials: M
authors.lastname: Jorda
authors.forename: Carlos
authors.initials: C
authors.lastname: Perez-Stable
authors.forename: Priyamvada
authors.initials: P
authors.lastname: Rai
mesh_terms: D000728:Androgens / Q000235:genetics* / Q000378:metabolism*; D016923:Cell Death / Q000235:genetics; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D000728:Androgens; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein