The role of Piwi porteins in aging and in tumor formation

Our research focuses on investigating the new biological functions of Piwi (P-element Induced WImpy testis in Drosophila) porteins and their potential medical applications. Piwi proteins together with Piwi-interacting RNAs (piRNAs) form a specific molecular machinery, the primary function of which is to control and block mobile genetic elements (MGEs), often called “jumping genes”. The movement of MGEs to new genomic loci results in insertional mutagenesis, so the Piwi-piRNA genetic pathway is essential in the maintenance of genome stability. The significance of this protective role is further underlined by the fact that approximately half of the human genome (47%) is made up of MGE-related repetitive sequences. The activity of the Piwi-piRNA pathway was originally detected in immortal germline cells (cells that genetically connect subsequent generations) but interestingly, recent studies could also provide evidence that this pathway is active in all tumor cell lines examined so far, as well as in some stem cell-like somatic cells of certain low-class, non-aging animal species (such as freshwater hydras or planarias). The activity of Piwi proteins is therefore the characteristic of non-aging cells, having unlimited dividing potential. Piwi porteins could have a role in the inhibition of aging process (e.g. in immortal germ cells), and also in the establishment of unlimited proliferative potential of tumor (stem) cells. According to our hypothesis, cancer cells can only form tumors if they express Piwi poteins, so they “behave” similarly to germ cells. During our research program, we will inhibit or hyperactivate Piwi proteins in cells and in genetic model systems. The inhibition of Piwi proteins could inhibit cancer cell growth/survival by inducing genomic instability, whereas ectopic expression of Piwi proteins could slow down the rate of aging, thereby significantly increase life expectancy. In addition, we would like to identify and characterize potential drug molecules that slow down or block tumor formation by inhibiting Piwi activity. Our proposal is therefore targets two focus points of the “Synergy” research program: 1, The role of regulatory proteins in inflammatory diseases and tumor formations AND 2, The role of regulatory proteins in aging process(es).

Tibor Vellai  - Tamás Orbán