Targeting NF-κB RelA/p65 phosphorylation overcomes RITA resistance

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• p53 tumor suppressor inactivation is common in cancer.
• RITA reactivates p53 to induce cancer cell apoptosis but acquired resistance is a challenge.
• Understanding resistance mechanisms is crucial for improving RITA efficacy.

Purpose of the Study:

• To investigate the role of nuclear factor-κB (NF-κB) RelA/p65 phosphorylation in RITA sensitivity.
• To identify potential strategies for overcoming RITA resistance in cancer cells.

Main Methods:

• Analyzed site-differential phosphorylation of RelA/p65 in RITA-sensitive and resistant cells.
• Utilized phosphomimetic mutations and gene silencing to assess RelA/p65 function.
• Investigated the role of ATP-binding cassette transporter ABCC6 in RITA resistance.
• Evaluated RITA efficacy in mouse xenograft models.

Main Results:

• RelA/p65 phosphorylation patterns at Ser536, Ser276, and Ser468 correlate with RITA sensitivity.
• Phosphorylation mimicry at Ser536 resensitized resistant cells, while at Ser276 induced resistance.
• ABCC6 upregulation in resistant cells conferred RITA resistance.
• Modulating RelA/p65 phosphorylation and ABCC6 restored RITA sensitivity in resistant models.

Conclusions:

• Site-specific phosphorylation of RelA/p65 acts as a barcode for RITA chemosensitivity.
• Targeting RelA/p65 phosphorylation and ABCC6 offers a potential strategy to overcome RITA resistance.
• This finding may lead to improved therapeutic approaches for RITA-based cancer treatment.