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
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 ab...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-01-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/3/2040 |
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| author | Andrea Pelliccia Francesco Capradossi Francesca Corsi Greta Deidda Tarquini Emanuele Bruni Albrecht Reichle Francesco Torino Lina Ghibelli |
| author_facet | Andrea Pelliccia Francesco Capradossi Francesca Corsi Greta Deidda Tarquini Emanuele Bruni Albrecht Reichle Francesco Torino Lina Ghibelli |
| author_sort | Andrea Pelliccia |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T09:43:00Z |
| format | Article |
| id | doaj.art-a079f2bd47ec43e6bbee497015200b76 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T09:43:00Z |
| publishDate | 2023-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-a079f2bd47ec43e6bbee497015200b762023-11-16T16:51:29ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-01-01243204010.3390/ijms24032040Androgen Deprivation Freezes Hormone-Sensitive Prostate Cancer Cells in a Reversible, Genetically Unstable Quasi-Apoptotic State, Bursting into Full Apoptosis upon Poly(ADP-ribose) Polymerase InhibitionAndrea Pelliccia0Francesco Capradossi1Francesca Corsi2Greta Deidda Tarquini3Emanuele Bruni4Albrecht Reichle5Francesco Torino6Lina Ghibelli7Department of Biology, University of Rome “Tor Vergata”, 00133 Rome, ItalyDepartment of Biology, University of Rome “Tor Vergata”, 00133 Rome, ItalyDepartment of Biology, University of Rome “Tor Vergata”, 00133 Rome, ItalyDepartment of Biology, University of Rome “Tor Vergata”, 00133 Rome, ItalyDepartment of Biology, University of Rome “Tor Vergata”, 00133 Rome, ItalyDepartment of Internal Medicine III, Hematology and Oncology, University Hospital of Regensburg, 93053 Regensburg, GermanyDepartment of Systems Medicine, Medical Oncology, University of Rome “Tor Vergata”, 00133 Rome, ItalyDepartment of Biology, University of Rome “Tor Vergata”, 00133 Rome, ItalyAndrogen 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.https://www.mdpi.com/1422-0067/24/3/2040hormone-sensitive prostate cancerandrogen deprivation therapyapoptosisPARPquasi-apoptotic state |
| spellingShingle | Andrea Pelliccia Francesco Capradossi Francesca Corsi Greta Deidda Tarquini Emanuele Bruni Albrecht Reichle Francesco Torino Lina Ghibelli 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 hormone-sensitive prostate cancer androgen deprivation therapy apoptosis PARP quasi-apoptotic state |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | hormone-sensitive prostate cancer androgen deprivation therapy apoptosis PARP quasi-apoptotic state |
| url | https://www.mdpi.com/1422-0067/24/3/2040 |
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