Bmi-1 inhibition sensitizes head and neck cancer stem cells to cytotoxic chemotherapy

Le résumé fourni par la source

• Bmi-1 enhance the resistance of cancer stem cells to cytotoxic chemotherapy. • Therapeutic targeting of Bmi-1 inhibits chemotherapy-induced cancer stemness. • Preclinical data suggest that patients with head and neck cancer might benefit from therapeutic inhibition of Bmi-1. Cancer stem cells (CSC) drive therapeutic resistance and recurrence in head and neck squamous cell carcinoma (HNSCC). We and others have shown that treatment with cytotoxic chemotherapy agents ( e.g. Cisplatin, Carboplatin) induce Bmi-1 expression and increase the fraction of highly tumorigenic CSC in HNSCC. Notably, Bmi-1 is a master regulator of stem cell self-renewal and DNA repair. The purpose of this work was to test whether therapeutic inhibition of Bmi-1 sensitizes HNSCC cancer stem cells to chemotherapy. HNSCC cells (UM-SCC-1,-22A,-22B) were treated with Cisplatin or Carboplatin and subjected to stemness analyses to evaluate the impact of Bmi-1 on chemoresistance. We observed that both, shRNA-mediated Bmi-1 silencing or pharmacologic inhibition of Bmi-1 with the small molecule inhibitor PTC596, blocked chemotherapy-induced cancer stemness ( i.e. increase in the fraction of ALDH high CD44 high cells), CSC self-renewal ( i.e. orosphere formation) and inhibited protective DNA damage responses in HNSCC. Further, it is known that high IL-6 serum levels correlate with poor HNSCC patient survival, and that platinum-based therapies induce IL-6 signaling. Here, we observed that Bmi-1 silencing (or PTC596 treatment) inhibited the IL-6R/STAT3 signaling pathway even in presence of platinum-based cytotoxic agents ( i.e. Cisplatin, Carboplatin). In vivo , Bmi-1 inhibition with PTC596 suppressed Cisplatin-mediated increase in the fraction of ALDH high CD44 high cells (cancer stemness). Collectively, these preclinical results demonstrate that Bmi-1 is a key mediator of head and neck cancer stemness and suggest that HNSCC patients might benefit from treatment with a Bmi-1 inhibitor combined with a conventional chemotherapeutic agent.

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