Apoptosis and Cancer
Programmed cell death (apoptosis) is a physiological process controlling tissue homeostasis. However, dysregulation of apoptosis induces an uncontrolled proliferation of cancer cells leading to progressive disease and resistancy to conventional chemo- and radiotherapeutic therapies. Thus, during the last decades efforts have been made to identify tumor-specific genes and proteins that can be selectively targeted for cancer therapies. Some of these genes that might be promising for “targeted therapies” are involved as regulators in distinct cascades of apoptosis.
In general, the process of apoptotic cell death is initiated via an “intrinsic pathway” in which pro-apoptotic factors are released from the mitochondria into the cytoplasm and the “extrinsic pathway” which is mediated via death receptors. In addition, apoptosis can be induced by cellular stress such as endoplasmic reticulum stress (i.e. hypoxia, unfolded proteins) or DNA damage. All of these initiating pathways activate a cascade of intracellular cysteinyl-aspartate specific proteases, known as "caspases" which directly or indirectly lead to the typical morphological changes of apoptotic cells such as cell shrinkage, membrane blebbing and apoptotic body formation. To date, a large number of proteins have been discovered that regulate apoptosis, including death-inducing ligands and receptors of the TNF-superfamily. One of these TNF-family members is the Apo2L/TRAIL (TNF-related apoptosis inducing ligand). Upon binding of TRAIL to the death domain containing receptors TRAIL-R1/DR4 and TRAIL-R2/DR5/KILLER/TRICK2, the apoptotic machinery is set in motion. However, antagonistic TRAIL-R3/DcR1/TRID, lacking a cytoplasmic domain and TRAIL-R4/DcR2/TRUNDD, exhibiting only a truncated death domain, protect cells from pro-apoptotic TRAIL actions. In addition to the pro-apoptotic activities which make TRAIL a promising therapeutic anticancer agent, TRAIL can also activate pathways that promote tumor cell survival and proliferation as well as metastasis via the granscription factors NF-?B, protein kinase B/Akt and MAP-Kinase pathways. So far, several mechanisms have been identified that promote TRAIL resistance on different levels of the TRAIL pathway. These mechanisms include i.e. mutations of death receptors, overexpression of FLICE-like inhibitory protein, Bcl2 family proteins or Inhibitor of apoptosis (IAP) proteins. The knowledge about these signalling pathways that control the expression of pro-apoptotic and anti-apoptotic genes is important for the identification of novel therapeutic strategies against cancer.
Our laboratory investigates mechanisms that are involved in both the induction of apoptosis or resistance to apoptosis. In this context, our research focuses on distinct types of cancers originating from the gastroenteropancreatic and endocrine system. In addition, we study the molecular involvement of antiapoptotic proteins in metastatic cancer disease.
Prof. Dr. med. Andreas Krieg
Dr. med. Levent Dizdar