Dr. Brignola is in her 2nd year of the international Ph.D. program in "Nutraceuticals, functional foods, and human health" at the Department of Pharmacy - University of Naples “Federico II”. Dr. Brignola completed her Master’s degree in Pharmacy at the University of Naples “Federico II”. The research interest of Dr. Brignola is focused on the study of molecular mechanisms activated in response to chemotherapeutic treatments and the identification of their targets in different 2D and 3D cancer cell models suitably engineered in order to develop personalized anticancer therapies. Dr. Brignola is serving as a member of the Italian Society of Biochemistry and Molecular Biology and the European Association for Cancer Research.
Dysregulation of mRNA translation is a major feature of several pathological conditions characterized by disruption of tissue homeostasis and altered stress responses, including cancer. Aberrant function of components of the translation machinery, as well as eukaryotic translation initiation factors (eIFs), have been documented in a variety of human neoplastic disorders . Specifically, it has been demonstrated that translational reprogramming is correlated with the overexpression of the eIF4F complex, leading to increased cell proliferation, survival, and multidrug resistance (MDR) .
Ribosomal protein L3 (uL3) is a component of cytosolic ribosomes that plays a crucial role in both ribosome structure and function. Our research group has extensively studied the extra-ribosomal functions of uL3. In particular, we have identified uL3 as a stress sensing molecule essential for cellular response to certain chemotherapeutics in colorectal cancer cells lacking functional p53 [3,4]. Notably, uL3 downregulation is associated with alteration of the epithelial-mesenchymal transition program, increase in cell migration and proliferation, inhibition of apoptosis, and enhancement of autophagy. Alteration of these signaling pathways results in the development of MDR [5-7]. Furthermore, mass spectrometry results from previous GST pull-down experiments and co-immunoprecipitation assays demonstrated that eIF4A, a component of the eIF4F complex, specifically interacts with uL3 in vitro.
In this study, we aimed to elucidate the role of uL3 in translational reprogramming mediated by eIFs. For this purpose, the translational status of known mRNAs regulated by eIF4A (i.e. BCL2-family, Cyclins, and c-Myc mRNAs) has been analyzed by qPCR in p53 deleted colorectal cancer cells and in a derivative cell line stably silenced for uL3, resulting in 5-fluorouracil resistance. The influence of the uL3/eIF4A complex on “translatome” and associated mRNAs has been investigated by using the “ribosome profiling” technique and high-throughput analysis of ribosome-associated mRNAs. Results from these experiments will be presented.