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Aarti D Rohira, David M. Lonard, and Bert W O'Malley

Tissue parenchyma is the functional unit of an organ and all of the remaining cells within that organ collectively make up the tissue stroma. The stroma includes fibroblasts, endothelial cells, immune cells, and nerves. Interactions between stromal and epithelial cells are essential for tissue development and healing after injury. These interactions are governed by growth factors, inflammatory cytokines and hormone signaling cascades. The steroid receptor coactivator (SRC) family of proteins includes 3 transcriptional coactivators that facilitate the assembly of multi-protein complexes to induce gene expression in response to activation of many cellular transcription factor signaling cascades. They are ubiquitously expressed and are especially critical for the developmental function of steroid hormone responsive tissues. The SRCs are overexpressed in multiple cancers including breast, ovarian, prostate and endometrial cancers. In this review, we focus on the role of the SRCs in regulating the functions of stromal cell components responsible for angiogenesis, inflammation and cell differentiation.

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Yeon Jean Cho, Jiyeun E Lee, Mi Jin Park, Bert W O’Malley, and Sang Jun Han

The steroid receptor coactivator (SRC)-1 isoform/estrogen receptor (ER)-β axis has an essential role in endometriosis progression. In this context, therefore, bufalin was employed as a ‘tool compound’ to evaluate inhibitors of SRC in alternative endometriosis treatment. Bufalin effectively suppressed the growth of primary human endometrial stroma cells isolated from endometriosis patients compared to women without endometriosis and immortalized human endometrial epithelial and stromal cells expressing the SRC-1 isoform compared to their parental cells in vitro. In vivo, compared to the vehicle, bufalin treatment significantly suppressed the growth of endometriotic lesions in mice with surgically induced endometriosis because bufalin disrupted the functional axis of SRC-1 isoform/ERβ by increasing SRC-1 isoform protein stability, hyperactivating the transcriptional activity of the SRC-1 isoform and degrading the ERβ protein by proteasome 26S subunit, non-ATPase 2 in endometriotic lesions. Bufalin treatment elevated the apoptosis signaling in epithelial cells of endometriotic lesions. In stromal cells of endometriotic lesions, bufalin treatment increased the levels of pyroptosis markers (caspase 1 and the active form of interleukin 1β) and reduced proliferation. In addition, bufalin treatment increased the expression levels of endoplasmic reticulum-stress (ERS) markers (PKR-like ER kinase, protein disulfide isomerase and binding immunoglobulin) in endometriotic lesions. Collectively, the bufalin-induced disruption of the SRC-1 isoform/ERβ axis might induce apoptosis, pyroptosis and ERS signaling in endometriotic lesions, causing the suppression of endometriosis. Therefore, future generations of SRC-modulators could be employed as an alternative medical approach for endometriosis treatment.