Androgen Deprivation-Induced Senescence Promotes Outgrowth of Androgen-Refractory Prostate Cancer Cells

Dominick G A Burton, Maria G. Giribaldi, Anisleidys Munoz, Katherine Halvorsen, Asmita Patel, Merce Jorda, Carlos Perez-Stable, Priyamvada Rai

Research output: Contribution to journalArticle

15 Citations (Scopus)

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.

Original languageEnglish
Article numbere68003
JournalPLoS One
Volume8
Issue number6
DOIs
StatePublished - Jun 28 2013

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prostatic neoplasms
androgens
Refractory materials
Androgens
Prostatic Neoplasms
Cells
Tumors
neoplasms
Neoplasms
Cell Aging
neoplasm cells
Cell death
cells
cell death
Cell Death
Population

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Androgen Deprivation-Induced Senescence Promotes Outgrowth of Androgen-Refractory Prostate Cancer Cells. / Burton, Dominick G A; Giribaldi, Maria G.; Munoz, Anisleidys; Halvorsen, Katherine; Patel, Asmita; Jorda, Merce; Perez-Stable, Carlos; Rai, Priyamvada.

In: PLoS One, Vol. 8, No. 6, e68003, 28.06.2013.

Research output: Contribution to journalArticle

Burton, Dominick G A ; Giribaldi, Maria G. ; Munoz, Anisleidys ; Halvorsen, Katherine ; Patel, Asmita ; Jorda, Merce ; Perez-Stable, Carlos ; Rai, Priyamvada. / Androgen Deprivation-Induced Senescence Promotes Outgrowth of Androgen-Refractory Prostate Cancer Cells. In: PLoS One. 2013 ; Vol. 8, No. 6.
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