The Response of Tumor Cells to Stress and Chemotherapy

1. The Response of Tumor Cells to Stress and Chemotherapy The Role of PKC Etta Livneh Faculty of Health Sciences

2. PKCeta confers protection against cell death • Primarily expressed in epithelial tissues and cells with high turn-over. Epithelia-the origin for 90% of tumors. Protects from cell death (Abu-Ghanem et al 2007, Rotem-Dai et al 2009, Karp et al 2007, Raveh-Amit et al 2011, Shahaf et al 2012). • In breast cancer patients-Its upregulation and localization in the cell membranes and the nuclear envelope predicts response to treatment. (Karp et al 2012). • In NSCLC patients - PKCeta is a novel prognostic marker. (Krasnitsky et al 2012). • Unique intracellular localization: ER/Golgi and cytoplasm. Shuttles between the cytoplasm and the nucleus and is tethered to the nuclear envelope upon DNA damage. (Maissel et al. 2006; Tamarkin et al. 2011).

3. PKCeta translocates to the NE in response to DNA Damage • Only the C1b domain is sufficient for protection against cell death • What is the entity that is formed in the membrane that tethers PKCeta to the membrane? • What is the signalling pathway activated in the membrane?

4. Role of PKC in authophagy and senescence • PKCeta is involved in cell cycle regulation at G1/S phase (Fima et al 2001, Fishman et al 1998, Kashiwagi et al 2000, Livneh et al 1996, Livneh and Fishman 1997, Shtutman et al 2003). • PKCeta is an upstream regulator of NFkB (Raveh-Amit et al 2011) • PKCeta induces secretion of IL-6 in fibroblasts (Fima et al 1999). • Premature senescence is enhanced by PKCeta in response to oxidative stress and DNA damage. • The polymorphic variant 374I (associated with cerebral infarction, Rheumatoid Arthritis (RA), gastric atrophy) more active as a kinase, is more effective in IL-6 secretion, the expression of the cell cycle inhibitor p21 and b-Gal staining supporting the role of PKCeta in senescence.

5. Cellular Senescence in Hodgkin's Lymphoma In collaboration with J. Gopas and D. BenHarroch

6. PKCeta is expressed in astrocytes in AD mice model is found near Ab plaques APP/PS1 - Cortex PKCη GFAP Ab Merge In collaboration with A. Monsonego

7. Novel regulation at the translational level via upstream open reading frames (uORFs): Role in response to stress • Are the peptides translated? • Do they have a biological function? • Different regulation in normal and tumor cells. • In CSC? In collaboration with M. Shapira

8. Looking for collaboration in the following areas: 1. We have shown a novel mode of regulation of the expression of proteins via uORFs in the 5'UTR of the mRNA (ongoing collaboration with Prof. Michal Shapira). As we suggest that the translation of peptides is involved in this regulation, we are also interested in sensitive methods for the detection and separation of peptides. 2. In the last years we have focused on the role of PKC in the protection against cell death. We are interested in collaboration on signaling pathways involved in apoptosis, authophagy and senescence. 3. We are interested in mice models of breast cancer or glioblastoma to explore the role of cancer stem cells (CSCs). 4. Design of novel inhibitors for protein kinases (small molecules or peptides) and high throughput screening for their screening