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Bcl-2-dependent modulation of Ca(2+) homeostasis and store-operated channels in prostate cancer cells
Fabien Vanden Abeele1, Roman Skryma, Yaroslav Shuba
1Laboratoire de Physiologie Cellulaire, INSERM EPI-9938, Universite des Sciences et Technologies de Lille, Batiment SN3, 59655 Villeneuve d'Ascq Cedex, France.
Abstract:
Antiapoptotic oncoprotein Bcl-2 has extramitochondrial actions due to its localization on the endoplasmic reticulum (ER); however, the specific mechanisms of such actions remain unclear. Here we show that Bcl-2 overexpression in LNCaP prostate cancer epithelial cells results in downregulation of store-operated Ca(2+) current by decreasing the number of functional channels and inhibiting ER Ca(2+) uptake through a reduction in the expression of calreticulin and SERCA2b, two key proteins controlling ER Ca(2+) content. Furthermore, we demonstrate that Ca(2+) store depletion by itself is not sufficient to induce apoptosis in Bcl-2 overexpressing cells, and that sustained Ca(2+) entry via activated store-operated channels (SOCs) is required as well. Our data therefore suggest the pivotal role of SOCs in apoptosis and cancer progression.
Insights
Bcl-2 protein overexpression in prostate cancer cells disrupts calcium signaling by reducing endoplasmic reticulum calcium uptake and store-operated channels, impacting apoptosis and cancer progression.
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Research
Background:
- The antiapoptotic oncoprotein Bcl-2, known for its mitochondrial roles, also exerts extramitochondrial functions at the endoplasmic reticulum (ER).
- The precise mechanisms underlying Bcl-2's non-canonical actions, particularly at the ER, remain incompletely understood.
- Understanding these mechanisms is crucial for elucidating Bcl-2's role in cellular processes beyond apoptosis regulation.
Purpose of the Study:
- To investigate the impact of Bcl-2 overexpression on calcium (Ca2+) handling within the endoplasmic reticulum.
- To elucidate the role of store-operated channels (SOCs) in apoptosis regulation in the context of Bcl-2 overexpression.
- To determine the contribution of ER Ca2+ content and Ca2+ influx to apoptosis in prostate cancer cells overexpressing Bcl-2.
Main Methods:
- Utilized LNCaP prostate cancer epithelial cells with Bcl-2 overexpression.
- Measured store-operated Ca2+ current and analyzed expression of key ER proteins, calreticulin and SERCA2b.
- Assessed the necessity of Ca2+ store depletion and sustained Ca2+ entry for apoptosis induction.
Main Results:
- Bcl-2 overexpression led to a downregulation of store-operated Ca2+ current.
- Reduced expression of calreticulin and SERCA2b was observed, inhibiting ER Ca2+ uptake.
- Apoptosis induction in Bcl-2 overexpressing cells required sustained Ca2+ entry via SOCs, not just Ca2+ store depletion.
Conclusions:
- Bcl-2 influences cellular calcium homeostasis by modulating ER Ca2+ content and SOC activity.
- Store-operated channels (SOCs) play a critical role in mediating apoptosis in prostate cancer cells with Bcl-2 overexpression.
- These findings highlight the significance of SOCs in both apoptosis and cancer progression, offering potential therapeutic targets.