The effect of estrogen on prolidase-dependent regulation of HIF-1α expression in breast cancer cells

Abstract

The role of estrogen in breast cancer progression and activation of prolidase activity and HIF-1α led us to study the effect of estrogen on nuclear HIF-1α expression in breast cancer estrogen-dependent MCF-7 and estrogen-independent MDA-MB-231 cells. We have found that in MCF-7 cells (expressing α and β estrogen receptor) cultured without estrogen receptor activator (phenol red, estradiol), HIF-1α was down-regulated, compared to the cells cultured with estrogen receptor activator. This effect was not observed in MDA-MB-231 cells (expressing only β estrogen receptor), suggesting that α estrogen receptor is involved in down-regulation of HIF-1α. However, in MDA-MB-231 cells (expressing high prolidase activity) cultured in the presence of prolidase substrates, Gly-Pro or Gly-HyPro, HIF-1α expression was induced in a dose-dependent manner, independently of estrogen receptor activation. In MCF-7 cells (with constitutively low prolidase activity) the effect of studied iminodipeptides on HIF-1α expression was much less pronounced but it was estrogen-dependent, showing importance of prolidase activity in mechanism of this process. The data were supported by confocal microscopy bio-imaging of HIF-1α in nucleus of MCF-7 and MDA-MB-231 cells that were cultured in the presence and absence of estrogen activator and prolidase substrates. It suggests that estrogen receptor may represent important therapeutic target in pharmacotherapy of estrogen receptor positive breast cancer, while ECM degradation enzymes, including prolidase may represent target in pharmacotherapy of estrogen receptor negative breast cancers.

Differential relationship between two hypoxia markers: HIF-1α and GLUT1 and classic prognostic factors in invasive breast carcinoma

“…Additionally, HIF-1α proteosomal degradation may be the result of the expression of either von Hippel-Lindau E3 ubiquitin-ligase (9) or Sharp-1, a basic helix-loop-helix transcription factor (24) . Molecular studies by Surazynski et al might be to some extent a confirmation of our findings on the relationship between HIF-1α and ER (25) . The authors suggested that α-estrogen receptor up-regulates the activity of prolidase, which in turn contributes to an increase in HIF-1α nuclear localization.…”

Functional Consequences of Intracellular Proline Levels Manipulation Affecting PRODH/POX–Dependent Pro-Apoptotic Pathways in a Novel in Vitro Cell Culture Model

“…Proline, by inhibition of HIF prolyl hydroxylase activity [4] suppresses proteosomal degradation of HIF-1α and increases HIF-1α transcriptional activity [4, 7, 47]. Therefore, increase in cytoplasmic proline concentration, which mostly depends on prolidase activity, contributes to increase in HIF-1α transcriptional activity [4].…”

Hypoxia‑inducible factor 1 mediates intermittent hypoxia‑induced migration of human breast cancer MDA‑MB‑231 cells

“…Triple-negative breast cancers (TNBCs), which are characterized by lacking expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor2 (HER2), comprise 15–20% of breast cancer cases and are considered the most malignant subtype, with the highest risk of metastasis ( 2 ). TNBCs more frequently disseminate to the distant organs, including brain, lung and liver, than to regional lymph nodes ( 2 , 3 ). Metastasis is regarded as the key contributor to breast cancer-associated mortality.…”