3D Tissue Models

Stig Linder

TypeWhite Paper Summary

Our group is interested in mechanisms of drug-induced cell death. Despite wide clinical use, the precise molecular mechanisms of action of cytostatic drugs are not known. We are studying platinum compounds and have shown that cisplatin, despite being a DNA damaging agent, has a cytoplasmic target (Mandic et al., J Biol Chem 2003). Our data show that DNA damage induces senescence, whereas apoptosis is induced by a reactive oxygen dependent cytoplasmic signaling pathway (Berndtsson et al., Int J Cancer 2006). Recent studies have shown that cisplatin induces at least two different stress-activated kinase pathways to regulate activation and complex formation of the pro-apoptotic mitochondrial protein BAK (Ihrlund Strandberg et al. Exp Cell Res 2006). Induction of reactive nitrogen and oxygen species is another mechanism of potential importance in chemotherapy-induced apoptosis. We study drug- and cell-specific nitration and carbonylation of cellular proteins, and how this affects the mode and the extent of cell death in different types of cells. The involvement of these mechanisms in the toxic side effects of, e.g., cisplatin, is also addressed. We are in the process of characterizing a large set of pro-apoptotic compounds with respect to their mechanisms of action. Interestingly, compounds that induce p53-independent apoptosis have been found to induce lysosomal membrane permeabilization (Erdal et al., PNAS 2005). In a more clinically oriented project we study tumor cell death in patient serum. Our data show that many tumors die by necrosis and not apoptosis (Kramer et al., Cancer Res 2004). We are developing this technology for use as a tool for treatment montoing. In a recent study, we were able to use this method to study how docetaxel induces apoptosis during treatment of patients with prostate cancer (Kramer et al., Br J Cancer Res 2006). Interestingly, docetaxel was found to induce apoptosis in multiple treatment cycles, which may explain the clinical efficiency of this agent. Finally, we are studying the aspartyl protease napsin. We have shown that napsin is a prosurfactant B-convertase (Ueno et al., J Biol Chem 2004) and we are now studying other aspects of the biology of this protease. Responsible for information: Monica Ringheim [search]

Name:Stig Linder
Organization:Karolinska Institute

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