We previously showed that N6L, a pseudopeptide that targets
nucleolin, impairs pancreatic ductal
adenocarcinoma (PDAC) growth and normalizes
tumor vessels in animal models. In this study, we analyzed the translatome of PDAC cells treated with N6L to identify the pathways that were either repressed or activated. We observed a strong decrease in global
protein synthesis. However, about 6% of the mRNAs were enriched in the polysomes. We identified a 5'TOP motif in many of these mRNAs and demonstrated that a chimeric
RNA bearing a 5'TOP motif was up-regulated by N6L. We demonstrated that N6L activates the mTOR pathway, which is required for the translation of these mRNAs. An inhibitory synergistic effect in PDAC cell lines, including patient-derived xenografts and
tumor-derived organoids, was observed when N6L was combined with
mTOR inhibitors. In conclusion, N6L reduces pancreatic cells proliferation, which then undergoes translational reprogramming through activation of the mTOR pathway. N6L and
mTOR inhibitors act synergistically to inhibit the proliferation of PDAC and human PDX cell lines. This combotherapy of N6L and
mTOR inhibitors could constitute a promising alternative to treat
pancreatic cancer.