Abstract
Neuroendocrine (NE) differentiation is a hallmark of advanced, androgen-independent prostate cancer, for which there is no successful therapy. NE tumor cells are nonproliferating and escape apoptotic cell death; therefore, an understanding of the apoptotic status of the NE phenotype is imperative for the development of new therapies for prostate cancer. Here, we report for the first time on alterations in intracellular Ca2+ homeostasis, which is a key factor in apoptosis, caused by NE differentiation of androgen-dependent prostate cancer epithelial cells. NE-differentiating regimens, either cAMP elevation or androgen deprivation, resulted in a reduced endoplasmic reticulum Ca2+-store content due to both SERCA 2b Ca2+ ATPase and luminal Ca2+ binding/storage chaperone calreticulin underexpression, and to a downregulated store-operated Ca2+ current. NE-differentiated cells showed enhanced resistance to thapsigargin- and TNF-α-induced apoptosis, unrelated to antiapoptotic Bcl-2 protein overexpression. Our results suggest that targeting the key players determining Ca2+ homeostasis in an attempt to enhance the proapoptotic potential of malignant cells may prove to be a useful strategy in the treatment of advanced prostate cancer.
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Abbreviations
- NE:
-
neuroendocrine
- LNCaP:
-
lymph node carcinoma of the prostate
- ER:
-
endoplasmic reticulum
- I SOC :
-
store-operated Ca2+ current
- TG:
-
thapsigargin
- NSE:
-
neuron-specific enolase
- Bt2cAMP:
-
dibutyryl cAMP
- IBMX:
-
isobutylmethylxanthine
- SOCE:
-
store-operated Ca2+ entry
- ctrl-LNCaP:
-
control LNCaP cell
- NE-cAMP-LNCaP:
-
LNCaP cells differentiated into NE phenotype by [cAMP]in elevation
- NE-Andr(−)-LNCaP:
-
LNCaP cells differentiated into NE phenotype by androgen deprivation
- TUNEL technique:
-
terminal deoxynucleotide transferase-mediated dUTP-biotin nick-end labelling
- IAP:
-
inhibitor of apoptosis
- CRT:
-
calreticulin
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Acknowledgements
This work was supported by grants from INSERM, La Ligue Nationale Contre le Cancer and l'ARC (France), Association pour la Recherche sur les Tumeurs de la Prostate (ARTP), Fondation pour la Recherche Médicale (FRM), and INTAS-99-01248. YM Shuba was supported by INSERM and the French Ministry of Science.
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Vanoverberghe, K., Vanden Abeele, F., Mariot, P. et al. Ca2+ homeostasis and apoptotic resistance of neuroendocrine-differentiated prostate cancer cells. Cell Death Differ 11, 321–330 (2004). https://doi.org/10.1038/sj.cdd.4401375
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DOI: https://doi.org/10.1038/sj.cdd.4401375
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