Pelliccia, Andrea and Capradossi, Francesco and Corsi, Francesca and Tarquini, Greta Deidda and Bruni, Emanuele and Reichle, Albrecht and Torino, Francesco and Ghibelli, Lina (2023) Androgen Deprivation Freezes Hormone-Sensitive Prostate Cancer Cells in a Reversible, Genetically Unstable Quasi-Apoptotic State, Bursting into Full Apoptosis upon Poly(ADP-ribose) Polymerase Inhibition. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 24 (3): 2040. ISSN , 1422-0067
Full text not available from this repository. (Request a copy)Abstract
Androgen deprivation therapy (ADT) is a powerful treatment for metastatic hormone-sensitive prostate cancer (mHSPC) patients, but eventually and inevitably, cancer relapses, progressing to the fatal castration-resistant (CR)PC stage. Progression implies the emergence of cells proliferating in the absence of androgen through still elusive mechanisms. We show here for the first time that ADT induces LNCaP mHSPC cells to collectively enter a metastable quasi-apoptotic state (QUAPS) consisting of partial mitochondrial permeabilization, limited BAX and caspase activation, and moderate induction of caspase-dependent dsDNA breaks; despite this, cells maintain full viability. QUAPS is destabilized by poly(ADP)-polymerase inhibition (PARPi), breaking off toward overt intrinsic apoptosis and culture extinction. Instead, QUAPS is rapidly and efficiently reverted upon androgen restoration, with mitochondria rapidly recovering integrity and cells collectively resuming normal proliferation. Notably, replication restarts before DNA repair is completed, and implies an increased micronuclei frequency, indicating that ADT promotes genetic instability. The recovered cells re-acquire insensitivity to PARPi (as untreated LNCaP), pointing to specific, context-dependent vulnerability of mHSPC cells to PARPi during ADT. Summarizing, QUAPS is an unstable, pro-mutagenic state developing as a pro-survival pathway stabilized by PARP, and constitutes a novel viewpoint explaining how ADT-treated mHSPC may progress to CRPC, indicating possible preventive countermeasures.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | RAT VENTRAL PROSTATE; DNA-DAMAGE; COMET ASSAY; CASTRATION; THERAPY; MECHANISMS; PATHWAYS; PROMOTES; REPAIR; ROLES; hormone-sensitive prostate cancer; androgen deprivation therapy; apoptosis; PARP; quasi-apoptotic state |
| Subjects: | 500 Science > 570 Life sciences 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin III (Hämatologie und Internistische Onkologie) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 23 Mar 2024 09:15 |
| Last Modified: | 23 Mar 2024 09:15 |
| URI: | https://pred.uni-regensburg.de/id/eprint/60383 |
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