Hypertonicity counteracts MCL‐1 and renders BCL‐XL a synthetic lethal target in head and neck cancer

Abstract

Head and neck squamous cell carcinoma (HNSCC) is an aggressive and difficult-to-treat cancer entity. Current therapies ultimately aim to activate the mitochondria-controlled (intrinsic) apoptosis pathway, but complex alterations in intracellular signaling cascades and the extracellular microenvironment hamper treatment response. On the one hand, proteins of the BCL-2 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 BH3-only protein NOXA in response to hyperosmotic stress. Induction of NOXA is sufficient to counteract the antiapoptotic properties of MCL-1 and switches HNSCC cells from dual BCL-XL/MCL-1 protection to exclusive BCL-XL addiction. Hypertonicity-induced functional loss of MCL-1 renders BCL-XL a synthetically lethal target in HNSCC, and inhibition of BCL-XL efficiently kills HNSCC cells that poorly respond to conventional therapies. We identify hypertonicity-induced 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. Abbreviations CI, combination index; EGFR, epidermal growth factor receptor; ER, endoplasmic reticulum; HNSCC, head and neck squamous cell carcinoma; OMM, outer mitochondrial membrane.

Physical Forces in Glioblastoma Migration: A Systematic Review

“…A wide range of techniques have been employed to study oncotic and hydrostatic pressures in cancer. Different cancer studies have included adenocarcinoma [ 66 ], breast [ 67 ], colorectal [ 68 ], esophageal [ 69 ], head and neck [ 70 ], lung [ 71 ], melanoma [ 68 ], ovarian [ 72 ], prostate [ 73 ], and skin [ 74 ]. The variations in hyper- and hypo-osmotic states contributing to the tumorgenicity of the different cancers demonstrates the importance of regulating homeostasis.…”

Myeloid cell leukemia-1 expression in cancers of the oral cavity: a scoping review

“…Despite evidence on the role of Mcl-1 as an important molecular target in oral cancer, the molecular mechanisms involved in oral cancer have not been well documented compared with those in other cancers. Isolated reports on the regulation and interactions of Mcl-1 in oral cancer have been identified [32,38,39]. The activity of Mcl-1 in oral cancer is found to be regulated by paracrine signaling mechanisms, physical forces, or intracellular regulatory mechanisms [28,39,40].…”

“…Isolated reports on the regulation and interactions of Mcl-1 in oral cancer have been identified [32,38,39]. The activity of Mcl-1 in oral cancer is found to be regulated by paracrine signaling mechanisms, physical forces, or intracellular regulatory mechanisms [28,39,40]. The Mcl-1 mRNA expression was upregulated by STAT3 activation and stabilized by Akt-mediated GSK3β inactivation in chemotherapy-resistant OSCC [38].…”

Linking hyperosmotic stress and apoptotic sensitivity

“…A notable exception is the group of Martin Ehrenschwender and colleagues, who analyse apoptosis susceptibility at isotonic and hypertonic conditions in cellular models of various cancers. In their latest work (Heimer et al ., [2]), they demonstrate that head and neck squamous cell carcinoma (HNSCC) cells respond to hypertonic stress by inactivating the protein Mcl‐1. Mcl‐1 is an antiapoptotic member of the Bcl‐2 protein family and, together with Bcl‐xL and Bcl‐2 itself, prevents the permeabilisation of the outer mitochondrial membrane by Bax and Bak, two pore‐forming proteins that initiate the execution phase of apoptosis [3].…”

“…A notable exception is the group of Martin Ehrenschwender and colleagues, who analyse apoptosis susceptibility at isotonic and hypertonic conditions in cellular models of various cancers. In their latest work (Heimer et al, [2]), they demonstrate that head and neck squamous cell carcinoma (HNSCC) cells respond to hypertonic stress by inactivating the protein Mcl-1.…”