Estrogen Attenuates Hypoxia-Induced TRPV1 Activation and Calcium Overload via HIF-1α Suppression in MCF-7 and CHO Cells

Abstract

Hypoxia is a major global health concern, particularly in premature infants and cancer, where it promotes intracellular calcium accumulation and cell death. The transient receptor potential vanilloid 1 (TRPV1) channel has been implicated in calcium dysregulation and oxidative stress under hypoxic conditions, while estrogen (17β-estradiol, E2) is known to modulate TRPV1 activity and redox balance. This study aimed to investigate the impact of E2 on TRPV1 expression, hypoxia-inducible factor-1α (HIF-1α), and calcium signaling in MCF-7 breast cancer cells (ERα-positive) and TRPV1-transfected CHO cells (ERα-negative). Four experimental groups were established: normoxia, E2, hypoxia, and hypoxia + E2. Hypoxia was induced by CoCl2 (200 µM, 24 h), while E2 treatment was applied at 10 nM for 24 h. Western blot analysis revealed that both TRPV1 and HIF-1α expression were upregulated under hypoxia but significantly reduced by E2. Fura-2 fluorescence assays revealed that hypoxia increased cytosolic Ca2+ levels, whereas E2 reversed this elevation. Moreover, TRPV1 activation by capsaicin induced marked Ca2+ influx under hypoxia, which was attenuated by E2 treatment. These findings demonstrate that E2 mitigates hypoxia-induced toxicity by modulating TRPV1-mediated Ca2+ signaling and HIF-1α expression, underscoring the protective role of E2 and identifying TRPV1 as a potential therapeutic target in estrogen-responsive tumors.