title: Inhibition of BMI1 induces autophagy-mediated necroptosis.
abstract: The clonal self-renewal property conferred by BMI1 is instrumental in maintenance of not only normal stem cells but also cancer-initiating cells from several different malignancies that represent a major challenge to chemotherapy. Realizing the immense pathological significance, PTC-209, a small molecule inhibitor of BMI1 transcription has recently been described. While targeting BMI1 in various systems significantly decreases clonal growth, the mechanisms differ, are context-dependent, and somewhat unclear. We report here that genetic or pharmacological inhibition of BMI1 significantly impacts clonal growth without altering CDKN2A/INK4/ARF or CCNG2 and induces autophagy in ovarian cancer (OvCa) cells through ATP depletion. While autophagy can promote survival or induce cell death, targeting BMI1 engages the PINK1-PARK2-dependent mitochondrial pathway and induces a novel mode of nonapoptotic, necroptosis-mediated cell death. In OvCa, necroptosis is potentiated by activation of the RIPK1-RIPK3 complex that phosphorylates its downstream substrate, MLKL. Importantly, genetic or pharmacological inhibitors of autophagy or RIPK3 rescue clonal growth in BMI1 depleted cells. Thus, we have established a novel molecular link between BMI1, clonal growth, autophagy and necroptosis. In chemoresistant OvCa where apoptotic pathways are frequently impaired, necroptotic cell death modalities provide an important alternate strategy that leverage overexpression of BMI1.
authors.affiliation: a Department of Obstetrics and Gynecology , Stephenson Cancer Center, University of Oklahoma Health Science Center , Oklahoma City , OK , USA.
authors.forename: Anindya
authors.initials: A
authors.lastname: Dey
authors.affiliation: a Department of Obstetrics and Gynecology , Stephenson Cancer Center, University of Oklahoma Health Science Center , Oklahoma City , OK , USA.
authors.forename: Soumyajit Banerjee
authors.initials: SB
authors.lastname: Mustafi
authors.affiliation: b Department of Pathology , Stephenson Cancer Center, University of Oklahoma Health Science Center , Oklahoma City , OK , USA.
authors.forename: Sounik
authors.initials: S
authors.lastname: Saha
authors.affiliation: a Department of Obstetrics and Gynecology , Stephenson Cancer Center, University of Oklahoma Health Science Center , Oklahoma City , OK , USA.
authors.forename: Shailendra
authors.initials: S
authors.lastname: Kumar Dhar Dwivedi
authors.affiliation: b Department of Pathology , Stephenson Cancer Center, University of Oklahoma Health Science Center , Oklahoma City , OK , USA.
authors.forename: Priyabrata
authors.initials: P
authors.lastname: Mukherjee
authors.affiliation: a Department of Obstetrics and Gynecology , Stephenson Cancer Center, University of Oklahoma Health Science Center , Oklahoma City , OK , USA.|c Department of Cell Biology , University of Oklahoma College of Medicine , Oklahoma City , OK , USA.
authors.forename: Resham
authors.initials: R
authors.lastname: Bhattacharya
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D006574:Heterocyclic Compounds, 2-Ring / Q000494:pharmacology; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D009336:Necrosis; D063150:Polycomb Repressive Complex 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology
chemical_list: C069077:BMI1 protein, human; D006574:Heterocyclic Compounds, 2-Ring; C586999:PTC-209; D013844:Thiazoles; D000255:Adenosine Triphosphate; D063150:Polycomb Repressive Complex 1; D020169:Caspases
keywords: BMI1; PTC-209; autophagy; necroptosis; ovarian cancer