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- W2093397186 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." @default.
- W2093397186 created "2016-06-24" @default.
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- W2093397186 date "2013-06-28" @default.
- W2093397186 modified "2023-10-17" @default.
- W2093397186 title "Androgen Deprivation-Induced Senescence Promotes Outgrowth of Androgen-Refractory Prostate Cancer Cells" @default.
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- W2093397186 doi "https://doi.org/10.1371/journal.pone.0068003" @default.
- W2093397186 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/3695935" @default.
- W2093397186 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/23840802" @default.
- W2093397186 hasPublicationYear "2013" @default.
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