Hypoxic Signaling Is Modulated by Calcium Channel, CaV1.3, in Androgen-Resistant Prostate Cancer

Area of Science:

• Oncology
• Molecular Biology
• Calcium Signaling

Background:

• Androgen deprivation therapy (ADT) is crucial for advanced prostate cancer (PCa) but can lead to castrate-resistant prostate cancer (CRPC).
• Hypoxic tumor microenvironments and hypoxia-inducible factor (HIF) signaling are implicated in CRPC development.
• Intracellular calcium, particularly store-operated calcium entry (SOCE) via CaV1.3, is modulated by ADT and may influence hypoxic signaling.

Purpose of the Study:

• To explore the role of the voltage-gated calcium channel, CaV1.3, in supporting hypoxic signaling and CRPC biology.
• To investigate the impact of ADT on CaV1.3 expression and SOCE.
• To determine how CaV1.3 affects HIF signaling and CRPC cell behavior under hypoxic conditions.

Main Methods:

• Cultured androgen-sensitive PCa LNCaP cells and ADT-resistant CRPC cells under normal and hypoxic (1% O2) conditions.
• Measured gene and protein expression of HIF-1α, CaV1.3, and androgen receptor (AR) using qPCR and Western blot.
• Assessed SOCE, cell proliferation, and cell survival with Fura-2AM fluorescence, WST-1 assay, and colony formation assays, respectively, with and without CaV1.3 inhibition (siCaV1.3).

Main Results:

• CaV1.3 expression and SOCE increased with ADT.
• HIF-1α was upregulated by ADT and further increased under hypoxia, with a greater fold change in resistant cells.
• CaV1.3 inhibition reduced HIF-1α and AR expression in ADT-sensitive cells but increased them in CRPC cells under hypoxia.
• CaV1.3 inhibition significantly reduced cell survival in all cell types under hypoxia and reduced proliferation in CRPC cells.

Conclusions:

• CaV1.3 modulates HIF signaling and impacts prostate cancer tumor biology under hypoxia.
• The precise mechanism by which CaV1.3 influences HIF signaling (via SOCE or noncanonical pathways) requires further investigation.
• CaV1.3 inhibition shows potential for reducing CRPC cell survival and proliferation, particularly under hypoxic conditions.