Reporter PET Images Bortezomib Treatment-Mediated Suppression of Cancer Cell Proteasome Activity

Area of Science:

• Oncology
• Molecular Imaging
• Biotechnology

Background:

• Proteasomal protein degradation is a key target in cancer therapy.
• Noninvasive imaging of proteasome activity is crucial for treatment monitoring.

Purpose of the Study:

• To develop a novel positron emission tomography (PET) imaging technique to visualize cancer cells with inhibited proteasome activity.
• To assess the efficacy of the NIS-cODC fusion gene system for monitoring proteasome inhibition.

Main Methods:

• Constructed a retroviral vector with the human sodium-iodide symporter (NIS) gene fused to the murine carboxyl-terminal of ornithine decarboxylase (cODC) degron (NIS-cODC).
• Utilized transient and stable transduction of colon cancer cells (CT26, HT29) with the NIS-cODC construct.
• Administered bortezomib to inhibit proteasome activity and measured NIS expression, radioisotope uptake (¹²⁵I, ⁹⁹mTc-O₄⁻, ¹²⁴I), and cell survival.
• Evaluated imaging in CT26/NIS-cODC tumor-bearing mice using PET scans.

Main Results:

• Inhibition of proteasome activity with bortezomib significantly increased NIS expression and radioiodide uptake in NIS-cODC expressing cancer cells.
• Bortezomib treatment demonstrated a dose-dependent correlation between radioisotope uptake and cancer cell survival.
• PET imaging of CT26/NIS-cODC tumors in mice showed increased ¹²⁴I uptake following bortezomib administration.
• Increased NIS expression was confirmed in tumor tissues from treated mice.

Conclusions:

• The NIS-cODC PET imaging system enables noninvasive visualization of proteasome inhibition in cancer cells.
• This technique holds potential for quantitative monitoring of proteasome inhibitor therapy, such as with bortezomib.
• NIS-cODC PET imaging may improve the management and efficacy assessment of targeted cancer therapies.