Abstract
Simple SummaryThe estrogen receptor (ER) status and the availability of agonists or antagonists of these receptors determine the processes of growth, differentiation, and proliferation of breast cancer cells. Estrogens and anti-estrogenic compounds have been shown to influence breast cancer cell survival/apoptosis via action through the mitochondrial enzyme proline dehydrogenase/proline oxidase (PRODH/POX). In this review, we highlight the molecular effects of ER stimulation/inhibition in signaling pathways.It has been suggested that activation of estrogen receptor α (ER α) stimulates cell proliferation. In contrast, estrogen receptor β (ER β) has anti-proliferative and pro-apoptotic activity. Although the role of estrogens in estrogen receptor-positive breast cancer progression has been well established, the mechanism of their effect on apoptosis is not fully understood. It has been considered that ER status of breast cancer cells and estrogen availability might determine proline dehydrogenase/proline oxidase (PRODH/POX)-dependent apoptosis. PRODH/POX is a mitochondrial enzyme that converts proline into pyrroline-5-carboxylate (P5C). During this process, ATP (adenosine triphosphate) or ROS (reactive oxygen species) are produced, facilitating cell survival or death, respectively. However, the critical factor in driving PRODH/POX-dependent functions is proline availability. The amount of this amino acid is regulated at the level of prolidase (proline releasing enzyme), collagen biosynthesis (proline utilizing process), and glutamine, glutamate, α-ketoglutarate, and ornithine metabolism. Estrogens were found to upregulate prolidase activity and collagen biosynthesis. It seems that in estrogen receptor-positive breast cancer cells, prolidase supports proline for collagen biosynthesis, limiting its availability for PRODH/POX-dependent apoptosis. Moreover, lack of free proline (known to upregulate the transcriptional activity of hypoxia-inducible factor 1, HIF-1) contributes to downregulation of HIF-1-dependent pro-survival activity. The complex regulatory mechanism also involves PRODH/POX expression and activity. It is induced transcriptionally by p53 and post-transcriptionally by AMPK (AMP-activated protein kinase), which is regulated by ERs. The review also discusses the role of interconversion of proline/glutamate/ornithine in supporting proline to PRODH/POX-dependent functions. The data suggest that PRODH/POX-induced apoptosis is dependent on ER status in breast cancer cells.
Highlights
Ligand binding causes dimerization of the receptor. This process is crucial for the formation of a functional transcription factor and the regulation of gene transcription interacting with the Estrogen Response Element (ERE)
Estrogens regulate proline dehydrogenase (PRODH)/Proline oxidase (POX)-dependent functions at the level of estrogen receptor (ER), p53, substrate availability for PRODH/POX that is dependent on prolidase activity and collagen biosynthesis, as well as HIF-1α
Estrogens may differentially affect PRODH/POX-induced functions pendently on the ERβ/ERα status. It seems that ERα has anti-apoptotic potential through dependently on the ERβ/ERα status
Summary
According to the WHO (World Health Organization) epidemiological data, for 2020, 19.3 million people developed cancer, and about 10 million people died. The cell models allow to strictly control conditions of the experiment in order to establish the critical factor affecting the studied processes They are especially helpful in case of limited availability of clinical samples or in vivo models (e.g., estradiol deficiency or estrogen receptor status). Ligand binding causes dimerization of the receptor This process is crucial for the formation of a functional transcription factor and the regulation of gene transcription interacting with the Estrogen Response Element (ERE). A ligand-independent signaling has been reported for ERα through kind of cross-talk with epidermal growth factor or insulin-like growth factor-I [16,17] Whether they are involved in PRODH/POX-dependent regulation of apoptosis/survival requires to be explored
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