Depleting the 19S proteasome regulatory PSMD1 subunit as a cancer therapy strategy

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Proteasome inhibitors are established cancer therapeutics targeting the 20S proteasome.
• Alternative strategies focus on inhibiting the 26S proteasome's deubiquitinating activity.
• Our prior work demonstrated reducing the 26S/20S ratio by depleting 19S proteasome subunits (PSMD1, 6, 11) effectively targets cancer cells dependent on this ratio.

Purpose of the Study:

• To evaluate the efficacy of PSMD1 depletion as a strategy to reduce the 26S/20S proteasome ratio in aggressive cancer models.
• To assess the impact of PSMD1 depletion on tumor growth in both cell line xenografts and patient-derived xenografts (PDX).

Main Methods:

• Utilized aggressive cancer cell lines (MDA-MB-231 triple-negative breast, OVCAR8 ovarian adenocarcinoma).
• Employed lentivectors for inducible and constitutive expression of PSMD1 short hairpin RNA (shRNA) in cell culture and xenograft models.
• Monitored tumor growth in mouse xenografts and PDX models following PSMD1 depletion.

Main Results:

• PSMD1 depletion, via shRNA, significantly inhibited tumor growth in MDA-MB-231 and OVCAR8 xenografts.
• The PSMD1 depletion strategy also effectively suppressed tumor growth in patient-derived ovarian cancer xenografts.
• Observed selective efficacy against aggressive cancer cells, with no detrimental effect on normal cells.

Conclusions:

• Reducing the 26S/20S proteasome ratio by targeting PSMD1 is a potent strategy against aggressive cancers.
• This approach holds potential for treating drug-resistant cancers that exhibit a high dependency on the 26S proteasome.
• The selective targeting of cancer cells suggests a favorable therapeutic window.