title: A High Concentration of Genistein Induces Cell Death in Human Uterine Leiomyoma Cells by Autophagy.
abstract: Genistein, an estrogenic, soy-derived isoflavone, may play a protective role against hormone-related cancers. We have reported that a high concentration of genistein inhibits cell proliferation and induces apoptosis in human uterine smooth muscle cells, but not in leiomyoma (fibroid) cells. To better understand the differential cell death responses of normal and tumor cells to a high concentration of genistein, we treated uterine smooth muscle cells and uterine leiomyoma cells with 50 μg/ml of genistein for 72 h and 168 h, and assessed for mediators of apoptosis, cytotoxicity and autophagy. We found that leiomyoma cells had increased protection from apoptosis by expressing an increased ratio of Bcl-2: bak at 72 h and 168 h; however, in smooth muscle cells, the Bcl-2: bak ratio was decreased at 72 h, but significantly rebounded by 168 h. The apoptosis extrinsic factors, Fas ligand and Fas receptor, were highly expressed in uterine smooth muscle cells following genistein treatment at both time points as evidenced by confocal microscopy. This was not seen in the uterine leiomyoma cells; however, cytotoxicity as indicated by elevated lactate dehydrogenase levels was significantly enhanced at 168 h. Increased immunoexpression of an autophagy/autophagosome marker was also observed in the leiomyoma cells, although minimally present in smooth muscle cells at 72 h. Ultrastructurally, there was evidence of autophagic vacuoles in the leiomyoma cells; whereas, the normal smooth muscle cells showed nuclear fragmentation indicative of apoptosis. In summary, our data show differential cell death pathways induced by genistein in tumor and normal uterine smooth muscle cells, and suggest novel cell death pathways that can be targeted for preventive and intervention strategies for inhibiting fibroid tumor cell growthin vivo.
authors: Molecular Pathogenesis Group, National Toxicology Program (NTP) Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health (NIH), Department of Health and Human Services (DHHS), Research Triangle Park, North Carolina 27709, USA.
authors: Lysandra
authors: L
authors: Castro
authors: Molecular Pathogenesis Group, National Toxicology Program (NTP) Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health (NIH), Department of Health and Human Services (DHHS), Research Triangle Park, North Carolina 27709, USA.
authors: Xioahua
authors: X
authors: Gao
authors: Molecular Pathogenesis Group, National Toxicology Program (NTP) Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health (NIH), Department of Health and Human Services (DHHS), Research Triangle Park, North Carolina 27709, USA.
authors: Alicia B
authors: AB
authors: Moore
authors: Molecular Pathogenesis Group, National Toxicology Program (NTP) Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health (NIH), Department of Health and Human Services (DHHS), Research Triangle Park, North Carolina 27709, USA.
authors: Linda
authors: L
authors: Yu
authors: School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors: Xudong
authors: X
authors: Di
authors: Biostatistics and Computational Biology Branch, Division of the Intramural Program (DIR) and NTP, National Institute of Environmental Health Sciences, National Institutes of Health (NIH), Department of Health and Human Services (DHHS), Research Triangle Park, North Carolina 27709, USA.
authors: Grace E
authors: GE
authors: Kissling
authors: Molecular Pathogenesis Group, National Toxicology Program (NTP) Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health (NIH), Department of Health and Human Services (DHHS), Research Triangle Park, North Carolina 27709, USA.
authors: Darlene
authors: D
authors: Dixon
keywords: Autophagy; Cell death; Concentration; Genistein; Uterine leiomyoma cells