24 research outputs found
Hypertonicity counteracts MCL 1 and renders BCL XL a synthetic lethal target in head and neck cancer
Head and neck squamous cell carcinoma (HNSCC) is an aggressive and difficultâtoâtreat cancer entity. Current therapies ultimately aim to activate the mitochondriaâcontrolled (intrinsic) apoptosis pathway, but complex alterations in intracellular signaling cascades and the extracellular microenvironment hamper treatment response. On the one hand, proteins of the BCLâ2 family set the threshold for cell death induction and prevent accidental cellular suicide. On the other hand, controlling a cell's readiness to die also determines whether malignant cells are sensitive or resistant to anticancer treatments. Here, we show that HNSCC cells upregulate the proapoptotic BH3âonly protein NOXA in response to hyperosmotic stress. Induction of NOXA is sufficient to counteract the antiapoptotic properties of MCLâ1 and switches HNSCC cells from dual BCLâXL/MCLâ1 protection to exclusive BCLâXL addiction. Hypertonicityâinduced functional loss of MCLâ1 renders BCLâXL a synthetically lethal target in HNSCC, and inhibition of BCLâXL efficiently kills HNSCC cells that poorly respond to conventional therapies. We identify hypertonicityâinduced upregulation of NOXA as link between osmotic pressure in the tumor environment and mitochondrial priming, which could perspectively be exploited to boost efficacy of anticancer drugs