The role of different cell death responses to DNA-damage treatment
Marijeta Kralj, dr.sc.
Chemotherapy remains the mainstay of cancer treatment. Although chemotherapeutics interfere with many cellular functions, their pivotal target is genomic DNA. Upon sensing the damage, cellular transducers activate signaling pathways that either temporarily halt the cell cycle, or execute lethal programs. It is well known that mutations in the cell cycle and death regulators are responsible for both tumorigenesis and chemoresistance. Because of extreme complexity of gene networks involved in cell proliferation and death, it is very hard to predict the response to therapy. Apoptosis is the best studied of the cellular responses, but there are also others, such as permanent growth arrest, or non-apoptotic death-mechanisms (necrosis, senescence, mitotic catastrophe). DNA-damage is one of the common causes to all these mechanisms, while p53 gene is their major regulator. It is the most frequently mutated gene in human tumors and loss of its function might induce drug resistance. We want to elucidate which modulators determine its tumor suppressive activities, and the role of other DNA-damage-induced genes, especially p21WAF1/CIP1, which is the main focus of our research. Its activation is involved in the response to many drugs, but its function is not completely clear: it plays a major role in cell senescence, but contradictory role in apoptosis. Therefore, we want to study its role in apoptosis and to investigate via which signaling factors it is related to other cell-death mechanisms. Also, we want to explore whether apoptosis, senescence and mitotic death are entirely independent programs, or they overlap and whether one mechanism can compensate for another that is inactivated.
The main goals of this project are:
- To correlate specific DNA lesion that is induced by antiutmor compounds with the final effect (specific cell response). Special emphasis is put on the importance of non-apoptotic responses to anticancer agents, such as cell senescence, mitotic catastrophe and autophagy and to the interdependency of apoptotic and non-apoptotic mechanisms.
- More precisely, we are interested in the role of p53 gene pathway, especially of p21WAF1/CIP1 gene that plays a major role in cell senescence, but contradictory role in apoptosis. We try to find out the mechanisms by which p21 gene arrests the cell cycle, regulate apoptosis, cellular senescence, autophagy and mitotic death and weather and how p21 characterize tumor cells with regard to chemosensitivity.
- These results should define whether and how p21 gene alone, or together with other cell cycle modulators that participate in the cell response to therapy, can be targeted by therapeutic strategies (gene therapy, antisense or small molecule therapy), and be manipulated towards regaining tumor suppression.