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The tumor environment critically influences responsiveness of cancer cells to chemotherapies, most of which activate the mitochondria-regulated (intrinsic) apoptotic cascade to kill malignant cells. Especially skin tumors encounter an environment with remarkable biophysical properties. Cutaneous accumulation of Na+ locally establishes osmotic pressure gradients in vivo (hypertonicity or hyperosmotic stress), but whether cutaneous hypertonicity is a factor that modulates the responsiveness of skin cancers to therapeutic apoptosis-induction has thus far not been investigated. Here, we show that hyperosmotic stress lowers the threshold for apoptosis induction in malignant melanoma, the deadliest form of skin cancer. Hypertonic conditions enforce addiction to BCL-2-like proteins to prevent initiation of the mitochondria-regulated (intrinsic) apoptotic pathway. Essentially, hyperosmotic stress primes mitochondria for death. Our work identifies osmotic pressure in the tumor microenvironment as a cell extrinsic factor that modulates responsiveness of malignant melanoma cells to therapy. [ABSTRACT FROM AUTHOR]

Death receptor 3 (DR3) was initially identified as a T cell co-stimulatory and pro-inflammatory molecule, but further studies revealed a more complex role of DR3 and its ligand TL1A. Although being a death receptor, DR3 gained to date predominantly attention as a contributor to inflammation-driven diseases. In our study, we investigated the cell death pathways associated with DR3. We show that in addition to apoptosis, DR3 can robustly trigger necroptotic cell death and provide evidence for TL1A-induced, DR3-mediated necrosome assembly. DR3-mediated necroptosis critically depends on receptor-interacting protein 1 (RIP1) and RIP3, the core components of the necroptotic machinery, which activate the pseudo-kinase mixed lineage kinase domain-like, the prototypic downstream effector molecule of necroptosis. Moreover, we demonstrate that DR3-mediated necroptotic cell death is accompanied by, but does not depend on generation of reactive oxygen species. In sum, we identify DR3 as a novel necroptosis-inducing death receptor and thereby lay ground for elucidating the (patho-) physiological relevance of DR3-mediated necroptotic cell death in vitro and in vivo. [ABSTRACT FROM AUTHOR]