Estrogen-Related Hormones Induce Apoptosis by Stabilizing Schlafen-12 Protein Turnover

Abstract

The mitochondrial pathway of apoptosis is controlled by the ratio of anti-and pro-apoptotic members of the Bcl-2 family of proteins. The molecular events underlying how a given physiological stimulus changes this ratio to trigger apoptosis remains unclear. We report here that human 17-b-estradiol (E2) and its related steroid hormones induce apoptosis by binding directly to phosphodiesterase 3A, which in turn recruits and stabilizes an otherwise fast-turnover protein Schlafen 12 (SLFN12). The elevated SLFN12 binds to ribosomes to exclude the recruitment of signal recognition particles (SRPs), thereby blocking the continuous protein translation occurring on the endoplasmic reticulum of E2-treated cells. These proteins include Bcl-2 and Mcl-1, whose ensuing decrease triggers apoptosis. The SLFN12 protein and an apoptosis activation marker were co-localized in syncytiotrophoblast of human placentas, where levels of estrogen-related hormones are high, and dynamic cell turnover by apoptosis is critical for successful implantation and placenta development.

Estrogen attenuates the growth of human papillomavirus positive epithelial cells

“…As expected, analysis of the response to estrogen in the sensitive HeLa cells revealed a significant increase in p53, pRb, γh2AX, and PARP1 cleavage (Figure 5A, top panel). Confirming the previously observed increase in apoptosis following estrogen in HeLa cells(23). Furthermore, analysis in the HPV-cancer cells reveals no dramatic alterations in p53, pRb, or PARP1 cleavage; however, there is a significant increase in γh2AX in C33a cells (Figure 5A, middle panel).…”

“…However, it soon became clear that our initial hypothesis was incorrect when HPV+ cells were specifically sensitized via estrogen treatment, while HPV-cells showed little to no response. We were also extremely surprised with the dramatic response to estrogen that we observed in HeLa cells, although recently published data now confirms our observations(23). This recent study utilizing HeLa cells as a model to analyze steroid signaling confirmed these cells are particularly sensitive to estrogen.…”

“…Previously, studies have shown that when E2 is overexpressed in HPV positive cervical cancer cells it represses transcription from the viral LCR and this repression reduces E6 and E7 levels and reactivates the p53 and pRb tumor suppressor proteins(31, 42–44, 44–50). Moreover, E2 overexpression and loss of E6/E7, results in the elevation of p53 and pRb that allows for previously observed attenuation of growth in HeLa cells(23, 31, 45, 46, 48). Similarly, our studies indicate estrogen treatment represses transcription from the LCR to reduce expression of E6 and E7 levels.…”

“…To further analyze estrogen treatment in HeLa, cells were treated with varying doses of estrogen for 48-hours, and subjected to a cell viability assay by monitoring ATP release via Cell Titer-Glo; as observed in (Figure 1Cii), estrogen significantly reduced HeLa cell viability at all doses tested. The recently published data by Li et al also observed this phenomena, and indicates that estrogen may provide a unique approach to attenuate the growth or to kill HPV+ cells(23).…”

“…These reports suggest ERα as a diagnostic marker but also raise the possibility of using estrogen as a therapeutic for the treatment of HPV+HNSCC. In support of the potential therapeutic potential of estrogen for HPV+ cancers, HeLa cells, an HPV18+ cervical cancer cell line, are extremely sensitive to estrogen treatment(22, 23). Given these recent reports we investigated the ability of estrogen to regulate the growth of HPV+ cell lines.…”