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Depletion of BMI1 Induces Autophagy Mediated Necroptosis
Author(s) -
Dey Anindya,
Banerjee Soumyajit,
Saha Sounik,
Dwivedi Shailendra,
Mukherjee Priyabrata,
Bhattacharya Resham
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1062.3
Subject(s) - necroptosis , autophagy , microbiology and biotechnology , biology , programmed cell death , bmi1 , pink1 , cancer research , mitophagy , ubiquitin ligase , cancer cell , kinase , parkin , cancer stem cell , stem cell , apoptosis , ubiquitin , cancer , genetics , medicine , pathology , gene , parkinson's disease , disease
The clonal self‐renewal property conferred by the polycomb complex protein BMI1 (BMI1 proto‐oncogene, polycomb ring finger) is instrumental in maintenance of not only normal stem‐cells but also cancer initiating cells from several different malignancies and represents a major challenge to chemotherapy. Realizing the immense pathologic significance, PTC‐209, a small molecule inhibitor of BMI1 transcription has recently been described. We report here that, genetic or pharmacologic inhibition of BMI1 significantly impacts clonal growth and induces autophagy in ovarian cancer (OvCa) cells through ATP depletion. While autophagy can promote survival or induce cell death, targeting BMI1 engages the PTEN induced putative kinase 1 (PINK1) ‐ parkin RBR E3 ubiquitin protein ligase (PARK2) dependent mitochondrial pathway and induces a novel mode of non‐apoptotic, necroptosis mediated cell death. In OvCa, necroptosis is potentiated by activation of the receptor (TNFRSF)‐interacting serine‐threonine kinase 1 (RIPK1) ‐ receptor‐interacting protein kinase 3 (RIPK3) complex that phosphorylates its downstream substrate, mixed lineage kinase domain‐like (MLKL). Importantly, genetic or pharmacologic inhibitors of autophagy or necroptosis rescue clonal growth in BMI1 depleted cells. Thus, we have established a novel molecular link between BMI1, clonal growth, autophagy and necroptosis. In chemo‐resistant OvCa where apoptotic pathways are frequently impaired, autophagy mediated necroptotic cell death modalities provide an important alternate strategy that leverage overexpression of BMI1. Support or Funding Information This study was supported by the National Institutes of Health (NIH) CA 157481 to RB.