The intrinsic or acquired resistance of tumor cells to cytostatic drugs is a major problem in tumor treatment. Many cytostatic drugs are effective by inducing DNA damage. This leads to apoptosis, a programmed cell death through certain signalling cascades. Sometimes cells protect themselves by repairing DNA damage or they block apoptosis efficiently. A promising approach on how to overcome tumor cell resistance is the introduction of alternative cell death pathways. Meanwhile, we know that cell death happens not only through apoptosis but also through diverse non-apoptotic ways termed as regulated necrosis.
Regulated necrosis means that cell death is morphologically similar to necrosis. It doesn’t run uncontrolled like the classic necrosis, but it can be controlled thorough pharmacological or genetic intervention. Ferroptosis is an example of regulated necrosis. It is triggered by lipid peroxidation, whereby iron plays an important role. Only a few ferroptosis triggers have been identified so far. To a great extent, the intracellular ferroptosis signalling cascades are unknown. We deal with the question of how and if ferroptosis can be triggered by reactive oxygen species. Reactive oxygen species plays a vital role in cancer formation and its treatment, heart attacks, atherosclerosis as well as in a few neurodegenerative diseases, such as Morbus Parkinson. The role of cell-cell contacts is another focus of research.
In healthy organisms, cell-cell contacts regulate proliferation and cell differentiation. The proliferation inhibition through cell-cell contacts is described as contact inhibition. Our work on the intracellular signalling cascade has contributed essentially to an understanding of this elementary regulation mechanism. Currently, the question arises as to what extent cell-cell contacts influence the sensitivity towards exogenous noxious agents such as reactive oxygen species and protect against cell death. This question is even more relevant, as tumor cells develop cell-cell contacts frequently which may influence sensitivity towards cytostatic agents. The possible tumor cell resistance based on cell-cell contacts has been little investigated.
Küppers M., Ittrich C., Faust D., Dietrich C. (2010) The transcriptional programme of contact-inhibition. Journal of Cellular Biochemistry, 110, 1234-1243
Faust D., Dolado I., Cuadrado A., Oesch F., Weiss C., Nebreda A., Dietrich C. (2005) p38 MAPK is required for contact-inhibition. Oncogene, 24, 7941-7945
Heit I., Wieser R., Herget T., Faust D., Borchert-Stuhlträger M., Oesch F., Dietrich C. (2001) Involvement of Protein kinase Cd in contact-dependent inhibition of growth in human and murine fibroblasts. Oncogene, 20, 5143-5154
Wieser R., Faust D., Dietrich C., Oesch F. (1999) p16ink4 mediates contact- inhibition of growth. Oncogene, 18, 277-281
Dietrich C., Wallenfang K., Oesch F., Wieser R. (1997) Difference in the mechanisms of growth control in contact-inhibited and serum-deprived human fibroblasts. Oncogene, 15, 2743-2747
Funding by the Rheinland-Pfalz Foundation for Innovation and the research fund of the University of Mainz
The aryl hydrocarbon receptor is known to be an endogenous transcription factor which is activated by environmental contaminants, such as polycyclic aromatic hydrocarbons (PAHs) and dioxins. Activation of the AhR leads to dimerization with ARNT (aryl hydrocarbon receptor nuclear translocator) and transcriptional activation of cytochrome P450 (CYP) enzymes , such as CYP1A1, CYP1A2 and CYP1B1. Induction of these genes leads to metabolic activation of PAHs to genotoxic compounds which explains their carcinogenic properties. However, dioxin one of the most potent tumor promotors ever tested in animal models - is not metabolised at all and the above mentioned induction of CYPs cannot account for the tumor promoting effects of dioxin. Hence, the role of the AhR in tumor promotion and cell cycle control still has to be elucidated. A review on this topic has been published recently.
Dietrich C., Kaina B. (2010) The aryl hydrocarbon receptor (AhR) in the regulation of cell - cell contact and tumor growth. Carcinogenesis, 31, 1319-1328
Loss of contact-inhibition is one characteristic feature of transformed cells. In rat liver oval cells, dioxin leads to a loss of contact-inhibition. To gain more insight into AhR-dependent signalling, we are analysing the molecular mechanisms of dioxin-dependent loss of contact-inhibition in these cells. We could show that dioxin leads to accumulation of the transcription factor JunD which in turn results in trasncriptional activation of the protooncogene cyclin A. This novel signalling pathway is possibly independent from ARNT. The relevance of this pathway in vivo is currently under investigation.
Weiss C., Faust D., Schreck I., Ruff A., Farwerck T., Melenberg A., Schneider S., Oesch-Bartlomowicz, B. Zatloukalova J., Vondracek J., Oesch F., Dietrich C. (2008) TCDD deregulates contact-inhibition in rat liver oval cells via AhR, JunD and Cyclin A. Oncogene, 27, 2198-2207
Andrysik Z., Vondracek J., Machala M., Krcmar A., Svihalkova-Sindlerova L., Kranz A., Weiss C., Faust D., Kozubik A., Dietrich C. (2007) The aryl hydrocarbon receptor-dependent deregulation of cell cycle control induced by polycyclic aromatic hydrocarbons in rat liver epithelial cells. Mutation Research, 615, 87-97
Dietrich C., Faust D., Moskwa M., Kunz A., Bock K., Oesch F. (2003) TCDD-dependent downregulation of g-catenin in rat liver epithelial cells (WB-F344). International Journal of Cancer, 103, 435-439
Dietrich C., Faust D., Budt S., Moskwa M., Kunz A., Bock K., Oesch F. (2002) 2,3,7,8- Tetrachlorodibenzo-p-dioxin-Dependent release from contact-inhibition in WB-F344 cells: involvement of cyclin A. Toxicolology and Applied Pharmacology, 183, 117-126
Funded by the EU (ECNIS, Network of Excellence of the European Union 6th Framework Program) and the DFG.