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P53 enhances apoptosis induced by doxorubicin only under conditions of severe DNA damage
- Publication Year :
- 2018
- Publisher :
- Taylor & Francis, 2018.
-
Abstract
- We previously demonstrated that Bim is the main BH3-only protein replacing Bak/Bax from Bcl-xl to activate apoptosis in a p53-independent manner in response to doxorubicin in prostate cancer. However, the comparison of doxorubicin treatment between LNCaP cells carrying p53-wild type and PC3 cells carrying p53-null suggested that p53 might be essential for maximizing apoptosis. Inhibition of ATM did not affect doxorubicin-induced apoptosis. Overexpression of p53 did not affect ABT-263-induced apoptosis and nevertheless, the combination of doxorubicin with ABT-263 induced higher apoptotic responses than did doxorubicin or ABT-263 alone. These results advocated that doxorubicin-induced DNA damage controls p53 function for intensifying apoptosis. Indeed, overexpression of p53 only enhanced apoptosis under conditions of severe DNA damage induced by high concentrations of doxorubicin in LNCaP cells. Immunofluorescence staining showed vague γH2AX foci and enlarged nuclei in LNCaP cells in response to high concentrations of doxorubicin, en route to apoptosis. In addition, our results revealed that the apoptosis in response to DNA replication stress induced by CFS-1686, a catalytic inhibitor of topoisomerase, is p53-independent. Interestingly, the combination of doxorubicin with CFS-1686 generated DNA damage and replication stress simultaneously, resulting in a synergistic apoptotic effect in prostate cancer cells. Thus, we concluded that p53 is a sensor for enhanced apoptosis in response to DNA damage stress, not DNA replication stress, at least in prostate cancer.
- Subjects :
- Male
0301 basic medicine
DNA damage
Apoptosis
03 medical and health sciences
Prostate cancer
0302 clinical medicine
Cell Line, Tumor
LNCaP
medicine
Humans
Doxorubicin
Molecular Biology
bcl-2-Associated X Protein
biology
Topoisomerase
DNA replication
Prostatic Neoplasms
Cell Biology
medicine.disease
030104 developmental biology
Proto-Oncogene Proteins c-bcl-2
030220 oncology & carcinogenesis
biology.protein
Cancer research
Tumor Suppressor Protein p53
Function (biology)
DNA Damage
Signal Transduction
Research Paper
Developmental Biology
medicine.drug
Subjects
Details
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....15f2eed284fde96996f434245c858c87
- Full Text :
- https://doi.org/10.6084/m9.figshare.7067180