Endoplasmic reticulum Ca(2+) content decrease by PKA-dependent hyperphosphorylation of type 1 IP3 receptor...

Area of Science:

• Oncology
• Cell Biology
• Molecular Biology

Background:

• Advanced prostate cancer (PCa) treatment relies on androgen deprivation therapy (ADT).
• Tumor cells develop resistance to ADT, becoming hormone-refractory prostate cancer (HRPCa).
• Understanding HRPCa resistance mechanisms is crucial for developing effective therapies.

Purpose of the Study:

• To investigate the role of calcium homeostasis alterations in HRPCa cells during androgen deprivation.
• To identify molecular mechanisms by which HRPCa cells evade apoptosis induced by ADT.

Main Methods:

• Utilized HRPCa-derived LNCaP cells.
• Assessed changes in endoplasmic reticulum (ER) calcium ([Ca(2+)]ER) content.
• Investigated the role of inositol trisphosphate receptor type 1 (IP3R1) and its phosphorylation.
• Employed siRNA, pharmacological inhibitors (H89, TAT-peptide), and gene overexpression (SERCA2b).

Main Results:

• Androgen removal reduced [Ca(2+)]ER in HRPCa cells.
• This reduction was linked to increased IP3R1 levels and phosphorylation at Ser-1716, causing ER calcium leak.
• Restoring ER calcium via IP3R1 down-regulation or inhibited phosphorylation sensitized cells to ADT-induced apoptosis.
• SERCA2b overexpression counteracted ADT effects on ER calcium and reduced resistance.

Conclusions:

• Lowering ER calcium content through increased IP3R1 and PKA-mediated phosphorylation is a survival mechanism for HRPCa cells.
• Targeting IP3R1 phosphorylation presents a potential strategy to overcome ADT resistance in prostate cancer.