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.

Sodium butyrate inhibits migration and induces AMPK‐mTOR pathway‐dependent autophagy and ROS‐mediated apoptosis via the miR‐139‐5p/Bmi‐1 axis in human bladder cancer cells

“…Previous research found that depletion of Bmi‐1 genetically or pharmacologically led to AMPK‐activated autophagy and affected downstream biological behaviors . Our results showed that NaB depleted Bmi‐1 and triggered a marked increase in LC3B‐II, along with a decrease in p62 levels, in both cell lines (Figure E).…”

“…Interestingly, Bmi‐1 has been reported to be an important target of microRNAs that is closely relate to the reversal of EMT processes . In addition, depletion of Bmi‐1 pharmacologically and genetically induces cell death and triggers autophagy in other tumors …”

Relevance of necroptosis in cancer

“…The polycomb complex protein BMI‐1 has an essential role in regulating the proliferative activity of leukaemic stem cells and inhibiting its activity could be a potential therapeutic intervention in the clinic 68 . The BMI‐1 inhibitor PTC‐209 induced autophagy and RIPK3 upregulation leading to necroptosis of ovarian cancer cells 69 . Moreover, autophagy induced by chalcone resulted in cIAP1/2 degradation and formation of the ripoptosome that contributed to activate necroptosis to kill cancer cells 70 .…”

MDR1 mediated chemoresistance: BMI1 and TIP60 in action

“…Thus exposure to frontline platinum therapy induces resistance to drugs given in combination such as paclitaxel or as second-line such as doxorubicin. Therefore recently described small molecule inhibitors of BMI1 [24, 29] have the potential to alleviate acquired resistance to chemotherapy when applied in combination with first- or second-line drugs.…”