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Regulation of Bcl-2 during androgen-unresponsive progression of prostate cancer
C A Rothermund1, D Kondrikov, M-F Lin
1Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-4525, USA.
Abstract:
The progression of prostate cancer from androgen-responsive to an androgen-unresponsive state remains the greatest obstacle in the treatment of this disease. Androgen-unresponsive prostate cancer is highly resistant to chemotherapy and radiation treatment that kill cells by the induction of apoptosis. Elucidating the molecular mechanisms of apoptosis regulation in prostate cancer can be useful in the development of new strategies for effective therapy of androgen-unresponsive cancer. We analyzed the Bcl-2 family of apoptosis regulators using various passages of the LNCaP prostate cancer cell line, which serve as an in vitro model for the progression of prostate cancer from androgen-responsive to androgen-unresponsive. In our model, progressively higher passages of LNCaP cells represent the progression to androgen-unresponsiveness. We examined the basal mRNA expression of the Bcl-2 family of apoptosis regulators. Under normal growth conditions, both androgen-responsive and androgen-unresponsive LNCaP cells express the Bcl-2 family of genes at similar levels. Western blot analysis showed the presence of Bcl-2 protein in androgen-responsive cells but not in androgen-unresponsive cells. Both androgen-responsive and androgen-unresponsive cells expressed Bax protein at similar levels. When exposed to oxidative stress, androgen-responsive cells underwent apoptosis but androgen-unresponsive cells exhibited resistance suggesting that the progression to androgen-unresponsiveness was associated with altered regulation of apoptosis. Treatment with paclitaxel or sodium butyrate induced apoptosis in both androgen-responsive and androgen-unresponsive cells suggesting that the apoptotic machinery is still intact in androgen-unresponsive LNCaP cells.
Insights
Prostate cancer becomes resistant to treatment as it progresses. This study found that androgen-unresponsive prostate cancer cells lose Bcl-2 protein, impacting apoptosis regulation and treatment resistance.
Area of Science:
- Oncology
- Molecular Biology
- Cell Death Research
Background:
- Prostate cancer progression to an androgen-unresponsive state is a major treatment challenge.
- Androgen-unresponsive prostate cancer exhibits resistance to conventional therapies like chemotherapy and radiation.
- Understanding apoptosis regulation is crucial for developing new therapeutic strategies.
Purpose of the Study:
- To investigate the role of Bcl-2 family proteins in the transition of prostate cancer from androgen-responsive to androgen-unresponsive states.
- To identify molecular mechanisms underlying apoptosis resistance in advanced prostate cancer.
Main Methods:
- Utilized LNCaP prostate cancer cell line at various passages as an in vitro model for disease progression.
- Analyzed mRNA expression of Bcl-2 family genes under normal growth conditions.
- Performed Western blot analysis to assess Bcl-2 and Bax protein levels.
- Evaluated apoptosis induction in response to oxidative stress, paclitaxel, and sodium butyrate.
Main Results:
- Bcl-2 family gene mRNA levels were similar in both responsive and unresponsive cells.
- Bcl-2 protein was present in androgen-responsive cells but absent in androgen-unresponsive cells.
- Bax protein levels were comparable between responsive and unresponsive cells.
- Androgen-unresponsive cells showed resistance to oxidative stress-induced apoptosis but responded to paclitaxel or sodium butyrate.
Conclusions:
- The loss of Bcl-2 protein in androgen-unresponsive prostate cancer cells is associated with altered apoptosis regulation.
- Despite resistance to some stimuli, the apoptotic machinery remains functional in androgen-unresponsive cells.
- Targeting apoptosis pathways may offer therapeutic potential for advanced prostate cancer.