title: Enhancing chemotherapy response with Bmi-1 silencing in ovarian cancer.
abstract: Undoubtedly ovarian cancer is a vexing, incurable disease for patients with recurrent cancer and therapeutic options are limited. Although the polycomb group gene, Bmi-1 that regulates the self-renewal of normal stem and progenitor cells has been implicated in the pathogenesis of many human malignancies, yet a role for Bmi-1 in influencing chemotherapy response has not been addressed before. Here we demonstrate that silencing Bmi-1 reduces intracellular GSH levels and thereby sensitizes chemoresistant ovarian cancer cells to chemotherapeutics such as cisplatin. By exacerbating ROS production in response to cisplatin, Bmi-1 silencing activates the DNA damage response pathway, caspases and cleaves PARP resulting in the induction apoptosis in ovarian cancer cells. In an in vivo orthotopic mouse model of chemoresistant ovarian cancer, knockdown of Bmi-1 by nanoliposomal delivery significantly inhibits tumor growth. While cisplatin monotherapy was inactive, combination of Bmi-1 silencing along with cisplatin almost completely abrogated ovarian tumor growth. Collectively these findings establish Bmi-1 as an important new target for therapy in chemoresistant ovarian cancer.
authors: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota, United States of America.
authors: Enfeng
authors: E
authors: Wang
authors: Sanjib
authors: S
authors: Bhattacharyya
authors: Annamaria
authors: A
authors: Szabolcs
authors: Cristian
authors: C
authors: Rodriguez-Aguayo
authors: Nicholas B
authors: NB
authors: Jennings
authors: Gabriel
authors: G
authors: Lopez-Berestein
authors: Priyabrata
authors: P
authors: Mukherjee
authors: Anil K
authors: AK
authors: Sood
authors: Resham
authors: R
authors: Bhattacharya
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D049109:Cell Proliferation; D002945:Cisplatin / Q000627:therapeutic use*; D005260:Female; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D005978:Glutathione / Q000096:biosynthesis; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D063150:Polycomb Repressive Complex 1; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; C069077:BMI1 protein, human; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D017382:Reactive Oxygen Species; D012097:Repressor Proteins; D063150:Polycomb Repressive Complex 1; D005978:Glutathione; D002945:Cisplatin