Novel insights into the development of hormone resistance phenotype of prostate cancer cells
(2015)
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- Abstract
- Prostate cancer (PCa) is the most frequent cancer in men above the age of 50 years. Despite radical prostatectomy or radiation therapy as primary treatment, 15-30% of patients will develop an advanced or metastatic cancer requiring systemic therapies. Reference treatment of advanced PCa relies on pharmacological or surgical androgen deprivation therapy. However, despite initial efficacy of androgen deprivation (AD), the tumor inevitably adapts to low testosterone environment and becomes hormone refractory (HRPCa). A better understanding of the mechanisms of androgen independence is necessary to improve the management of HRPCa. Although autophagy confers chemoresistance in some cancers, its role in the development of HRPCa remained unknown. We found that AD or treatment with the anti-androgen bicalutamide promoted autophagy in HRPCa-derived LNCaP cells. This effect was associated with an inhibition of the PI3K/Akt/mTOR pathway and with a disruption of the complex formed by androgen receptor and the regulatory subunit of PI3K p85. Moreover, genetic or pharmacological inhibition of autophagy restored AD-dependent cell death indicating that autophagy is a protective mechanism against AD in HRPCa cells. Besides, in these same cells, we also observed different modifications of Ca2+ homeostasis after androgen withdrawal among which a reduction of the ER Ca2+ content. We discovered that the [Ca2+]ER decrease was due to the presence of IP3R1 made leakier by their phosphorylation by PKA inhibitor H89 or permeant TAT-peptide containing the Ser-1716 consensus phosphorylation sequence sensitized LNCaP cells to AD, suggesting that [Ca2+]ER can control HRPCa cells resistance to AD. Therefore, we identified two distinct mechanisms by which HRPCa-derived cells manage to overcome cell death that they face in the absence of androgenic stimulation. We hope that these findings will help to device new therapeutic strategies to circumvent hormone independence of advanced PCa.
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Boutin, B. (2015). Novel insights into the development of hormone resistance phenotype of prostate cancer cells. https://hdl.handle.net/2078.5/190254