p21 modulates threshold of apoptosis induced by DNA-damage and growth factor withdrawal in prostate cancer cells

Current therapy for advanced prostate cancer is largely based on androgen deprivation and is mostly palliative because all patients eventually relapse with androgen-independent disease. Doxorubicin (Dx), an anthracycline used commonly as a chemotherapeutic agent in relapsed prostate cancer, is a str...

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Bibliographic Details
Published in:Carcinogenesis (New York) 2002-08, Vol.23 (8), p.1289-1296
Main Authors: Martinez, Luis A., Yang, Jun, Vazquez, Elba S., del Carmen Rodriguez-Vargas, María, Olive, Matilde, Hsieh, Jer-Tsong, Logothetis, Christopher J., Navone, Nora M.
Format: Article
Language:English
Subjects:
Antibiotics, Antineoplastic - pharmacology
Antineoplastic agents
Apoptosis - physiology
Biological and medical sciences
CDK
Cell Cycle
Cell Survival
Chemotherapy
cyclin-dependent kinase
Cyclin-Dependent Kinase Inhibitor p21
Cyclins - metabolism
Cyclins - physiology
Cysteine Proteinase Inhibitors - pharmacology
DNA Damage
doxorubicin
Doxorubicin - pharmacology
Growth Substances - metabolism
HPV
human papillomavirus
Humans
Male
Medical sciences
MOI
multiplicities of infection
Neoplasms, Hormone-Dependent - metabolism
Neoplasms, Hormone-Dependent - pathology
Pharmacology. Drug treatments
Poly(ADP-ribose) Polymerases - metabolism
Prostatic Neoplasms - metabolism
Prostatic Neoplasms - pathology
Proto-Oncogene Proteins c-bcl-2 - physiology
terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick end labeling
Tumor Cells, Cultured
Tumor Suppressor Protein p53 - metabolism
TUNEL
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Summary:Current therapy for advanced prostate cancer is largely based on androgen deprivation and is mostly palliative because all patients eventually relapse with androgen-independent disease. Doxorubicin (Dx), an anthracycline used commonly as a chemotherapeutic agent in relapsed prostate cancer, is a strong inducer of p53 expression and p21CIP1/WAF1 (p21) transactivation. Previous reports suggest that p21 may have a role in the modulation to chemotherapy-induced apoptosis, prostate cancer progression and androgen regulation. In order to investigate if p21 has a pro-survival role in the response of prostate cancer cells to cellular stress, we exposed two androgen-regulated human prostate cancer cell lines (MDA PCa 2b and LNCaP) to Dx and growth factor withdrawal. We then studied expression of p53 and p21, cell-cycle kinetics and apoptosis. We have found that p53 protein accumulated in a dose- and time-dependent manner after Dx treatment, while p21 expression increased over time with low but decreased with high Dx doses. Apoptosis occurred in parallel with p21 down-modulation. Dx treatment of p53 knockout cells demonstrated that p21 induction was strictly p53 dependent. Reduction of p21 levels in prostate cancer cells with an antisense p21 adenovirus resulted in sensitization to Dx and accelerated onset of apoptosis in response to growth factor withdrawal. The evidence presented here also suggests that caspase activation mediates the apoptosis in this system and supports that p21 may modulate the threshold of apoptosis in prostate cancer. These observations may thus provide implications onto the integration of chemotherapy and androgen ablation.
ISSN:0143-3334
1460-2180
DOI:10.1093/carcin/23.8.1289