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Published on: February 16, 2015
Severe cellular stress drives apoptosis through a dual control mechanism independently of p53
Yen-Chun Wang1, Li-Ting Wang2, Ta I Hung3
1Department of Medical Education, Taipei Veterans General Hospital, Taipei, 11217, Taiwan.
Abstract:
For past two decades, p53 has been claimed as the primary sensor initiating apoptosis. Under severe cellular stress, p53 transcriptional activity activates BH3-only proteins such as Bim, Puma, or Noxa to nullify the inhibitory effects of anti-apoptotic proteins on pro-apoptotic proteins for mitochondrial outer membrane permeabilization. Cellular stress determines the expression level of p53, and the amount of p53 corresponds to the magnitude of apoptosis. However, our studies indicated that Bim and Puma are not the target genes of p53 in three cancer models, prostate cancer, glioblastoma, and osteosarcoma. Bim counteracted with Bcl-xl to activate apoptosis independently of p53 in response to doxorubicin-induced severe DNA damage in prostate cancer. Moreover, the transcriptional activity of p53 was more related to cell cycle arrest other than apoptosis for responding to DNA damage stress generated by doxorubicin in prostate cancer and glioblastoma. A proteasome inhibitor that causes protein turnover dysfunction, bortezomib, produced apoptosis in a p53-independent manner in glioblastoma and osteosarcoma. p53 in terms of both protein level and nuclear localization in combining doxorubicin with bortezomib treatment was obviously lower than when using DOX alone, inversely correlated with the magnitude of apoptosis in glioblastoma. Using a BH3-mimetic, ABT-263, to treat doxorubicin-sensitive p53-wild type and doxorubicin-resistant p53-null osteosarcoma cells demonstrated only limited apoptotic response. The combination of doxorubicin or bortezomib with ABT-263 generated a synergistic outcome of apoptosis in both p53-wild type and p53-null osteosarcoma cells. Together, this suggested that p53 might have no role in doxorubicin-induced apoptosis in prostate cancer, glioblastoma and osteosarcoma. The effects of ABT-263 in single and combination treatment of osteosarcoma or prostate cancer indicated a dual control to regulate apoptosis in response to severe cellular stress. Whether our findings only apply in these three types of cancers or extend to other cancer types remains to be explored.
Insights
The tumor suppressor p53 may not initiate apoptosis under severe stress, as Bim and Puma are not its targets. Instead, apoptosis can occur independently of p53, particularly with BH3-mimetics like ABT-263.
Area of Science:
- Cellular Biology
- Cancer Research
- Molecular Oncology
Background:
- The tumor suppressor p53 is traditionally considered the primary sensor for initiating apoptosis under cellular stress.
- p53 transcriptional activity is thought to activate BH3-only proteins (e.g., Bim, Puma, Noxa) to promote apoptosis via mitochondrial outer membrane permeabilization.
- The level of p53 expression and its activity often correlate with the magnitude of apoptosis.
Purpose of the Study:
- To investigate the role of p53 in apoptosis induction across different cancer types and stress conditions.
- To determine if Bim and Puma are direct transcriptional targets of p53 in prostate cancer, glioblastoma, and osteosarcoma.
- To explore alternative pathways regulating apoptosis, particularly in response to DNA damage and proteasome inhibition, and the efficacy of BH3-mimetics.
Main Methods:
- Analysis of p53 target genes in prostate cancer, glioblastoma, and osteosarcoma models.
- Assessment of apoptosis induction by doxorubicin (DNA damage) and bortezomib (proteasome inhibitor).
- Evaluation of apoptosis response using the BH3-mimetic ABT-263 in combination with chemotherapy agents in p53-wild type and p53-null cancer cells.
Main Results:
- Bim and Puma were found not to be direct p53 target genes in the studied cancer models.
- Doxorubicin-induced apoptosis in prostate cancer involved Bim acting independently of p53.
- p53 transcriptional activity was linked to cell cycle arrest rather than apoptosis in response to doxorubicin.
- Bortezomib induced apoptosis in a p53-independent manner in glioblastoma and osteosarcoma.
- Combination therapy with doxorubicin or bortezomib and ABT-263 synergistically induced apoptosis in both p53-wild type and p53-null osteosarcoma cells.
Conclusions:
- p53 may not play a significant role in doxorubicin-induced apoptosis in prostate cancer, glioblastoma, and osteosarcoma.
- Apoptosis regulation in response to severe cellular stress involves dual control mechanisms, including p53-independent pathways.
- BH3-mimetics like ABT-263 show potential for synergistic apoptosis induction when combined with chemotherapy, irrespective of p53 status.
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