Nucleolin Aptamer N6L Reprograms the Translational Machinery and Acts Synergistically with mTORi to Inhibit...

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with limited treatment options.
• N6L, a pseudopeptide targeting nucleolin, has shown potential in preclinical models by inhibiting PDAC growth and normalizing tumor vasculature.
• Understanding the molecular mechanisms of N6L action is crucial for developing effective therapies.

Purpose of the Study:

• To investigate the translatome of PDAC cells treated with N6L to identify affected pathways.
• To elucidate the role of the mTOR pathway in N6L-mediated translational reprogramming.
• To evaluate the synergistic effect of N6L combined with mTOR inhibitors in PDAC models.

Main Methods:

• Analysis of PDAC cell translatomes following N6L treatment.
• Identification and characterization of 5'TOP motif-containing mRNAs.
• Assessment of mTOR pathway activation by N6L.
• In vitro and in vivo evaluation of combination therapy with N6L and mTOR inhibitors.

Main Results:

• N6L treatment led to decreased global protein synthesis but enriched specific mRNAs with a 5'TOP motif.
• N6L was found to activate the mammalian target of rapamycin (mTOR) pathway.
• The combination of N6L and mTOR inhibitors demonstrated synergistic inhibition of PDAC cell proliferation in various models, including patient-derived xenografts and organoids.

Conclusions:

• N6L reduces pancreatic cancer cell proliferation through translational reprogramming mediated by mTOR pathway activation.
• Combination therapy with N6L and mTOR inhibitors shows significant promise for treating pancreatic cancer.
• This novel combotherapy offers a potential new therapeutic strategy for pancreatic cancer patients.