Role of uL3 in the translational reprogramming of 5-FU resistant colorectal cancer cells lacking functional p53

A large body of evidence has accumulated in recent years indicating that translational reprogramming is crucial in tumor initiation, invasion, and multidrug resistance (MDR). Several links have been made between the translation machinery and well-known oncogenes and tumor suppressors. Furthermore, changes in translation machinery components have been observed in a variety of human cancers. Translational reprogramming is frequently associated with alterations in eukaryotic translation initiation factors (eIFs) activity; in particular. the overexpression of the eIF4F complex components is correlated with MDR in melanoma, colon, and thyroid cancer cell lines. In our laboratory, we have extensively studied the extra-ribosomal functions of ribosomal protein uL3, which is a component of the large ribosomal subunit. Our findings revealed that uL3 plays a critical role in drug-induced ribosomal stress and MDR in colorectal and lung cancer cells lacking active p53. We have also shown that eIF4A, a component of the eIF4F complex, can interact with uL3. The goal of this research is to investigate the role of uL3 in translational reprogramming in HCT 116p53-/- cells and in a derivative cell line stably silenced for uL3, resulting in 5-FU resistance. To this end, translatome and associated mRNAs have been investigated in both cell lines treated or not with 5-FU by using "ribosome profiling" techniques and high-throughput analysis of ribosome-associated mRNAs. This approach will clarify the role of uL3 in translational reprogramming of colorectal cancer cells lacking functional p53 in response to drug-induced ribosomal stress and in chemoresistance. Results from these experiments will be presented.