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Published on: November 19, 2019
Cryoablative response of prostate cancer cells is influenced by androgen receptor expression
Daniel P Klossner1, John M Baust, Robert G VanBuskirk
1Institute of Biomedical Technology, SUNY, Binghamton, NY 13902, USA.
Objective:
To investigate in prostate cancer cells the consequences of androgen-insensitivity (AI) development on the cellular and molecular responses to freezing, as a challenge in prostate cancer treatment occurs when the androgen-sensitive (AS) phenotype switches to an AI phenotype, the latter of which is often refractory to many therapies.
Materials And Methods:
PC-3 (AI) and LNCaP (AS) were each genetically altered to express the opposite phenotype and subjected to an in vitro freezing model. Viability, caspase inhibitor and Western blot studies were used to determine the basis of the differential responses of AI and AS cells.
Results:
LNCaP high-passage cells, formed by repeated passage of LNCaP (AS) cells, were AI and showed a phenotypic shift to freeze resistance matching the freeze response of PC-3 cells (AI). While stably transfected androgen receptor (AR)-transfected cells (PC-3 AR) had a freezing sensitivity similar to that of the LNCaP (AS) cell line. Importantly, AI cell lines survived and recovered from freezing exposure to temperatures as low as -40 degrees C whereas AS cell lines did not. Caspase inhibition studies and related fluorescent probes showed an elevated level of apoptotic involvement in both AS cell lines after freezing compared with their AI counterparts. Western blot analysis showed that AR expression was modified after exposure to freezing.
Conclusion:
This study suggests that AS cancers may be far more sensitive to a freezing insult and this might be linked to elevated apoptosis and caspase activity. As such, cryoablation may prove most effective in cancer cells that have not yet progressed to a more resistant AI phenotype, but both generic variants can be fully ablated at sufficiently low temperatures.
Insights
Androgen-insensitive (AI) prostate cancer cells show increased resistance to freezing compared to androgen-sensitive (AS) cells, potentially due to lower apoptosis. Cryoablation may be more effective on AS cancers before they develop AI resistance.
Area of Science:
- Oncology
- Cell Biology
- Cryobiology
Background:
- Prostate cancer treatment faces challenges as androgen-sensitive (AS) tumors can become androgen-insensitive (AI).
- AI tumors are often refractory to therapies, necessitating alternative treatment strategies.
- Understanding cellular responses to physical insults like freezing is crucial for developing new therapeutic approaches.
Purpose of the Study:
- To investigate the impact of androgen-insensitivity (AI) development on prostate cancer cell responses to freezing.
- To compare the cellular and molecular mechanisms underlying the differential freezing responses of AI and AS prostate cancer cells.
- To assess the potential of cryoablation as a therapeutic strategy for different prostate cancer phenotypes.
Main Methods:
- Utilized PC-3 (AI) and LNCaP (AS) prostate cancer cell lines, genetically modified to express opposite phenotypes.
- Employed an in vitro freezing model to assess cell viability and responses.
- Conducted caspase inhibition studies and Western blot analysis to elucidate molecular mechanisms.
Main Results:
- Androgen-insensitive (AI) cell lines (PC-3 and high-passage LNCaP) exhibited significantly greater freeze resistance than androgen-sensitive (AS) cell lines.
- AI cells survived freezing down to -40°C, while AS cells did not.
- Elevated apoptosis and caspase activity were observed in AS cells post-freezing compared to AI cells, with modifications in androgen receptor (AR) expression noted.
Conclusions:
- Androgen-sensitive (AS) prostate cancers demonstrate higher sensitivity to freezing insults, linked to increased apoptosis and caspase activity.
- Cryoablation may be most effective against non-resistant AS cancer cells.
- Both AS and AI prostate cancer phenotypes can be eradicated at sufficiently low temperatures, suggesting cryoablation's broad applicability with temperature optimization.
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