PSMC2 overexpression

Besides, temozolomide resistance was associated with elevated proteasome activity that suppressed ER stress, which was restored upon inhibition of the proteasome with MG132. This boosted autophagosome nucleation, increased pro-death autophagy, and restored apoptosis in temozolomide-resistant glioblastoma cells. Finally, targeting PSMC2 provided a unique method for interrupting autophagy-mediated ER stress maintenance and temozolomide resistance in glioblastoma.

PSMC2 overexpression increases chymotrypsin-like proteasome activity at baseline in U266 and ARH77 cells with a similar effect of residual proteasome activity after challenge with bortezomib or carfilzomib. Taken together, our results suggest PSMC2 overexpression correlates with reduced OS in MM patients treated with bortezomib and that PSMC2 may represent an actionable therapeutic target to prevent or overcome PI resistance. PSMC2 overexpression increases proteasome activity in MM cells, mitigates ER stress on PI challenge and promotes PI resistance. mitigates ER stress upon PI challenge, and portending poorer clinical prognosis and more drug resistance, suggesting that 19S targeted agents may help overcome drug resistance in MM.

We postulated that the expression of clinically relevant proteasome subunits from MM cells correlated with reduced progression-free survival (PFS) and OS. We correlated the expression of proteasome genes with clinical outcomes using the APEX trial dataset, which compared the effect of bortezomib vs. steroid, and the MMRF COMMPASS trial...These cells exhibit higher levels of proteasome chymotrypsin-like activity activity (1.6-fold increase in ARH77 and 3-fold increase in U266 cells compared to controls; p< 0.01)... Taken together, our results demonstrate that PSMC2 and PSMC6 expression correlates with reduced OS in MM patients. Knockout of PSMC subunits decreased proteasome activity and increased dependence on autophagy, while PSMC upregulation increased proteasome activity and decreased PI sensitivity. Our work highlights the complex interplay of proteasome subunits in MM biology and suggests a prognostic and therapeutic role for 19S RP subunits in the anti-myeloma armamentarium.

PSMC2 and PSMC6 overexpressing cells were also resistant to PI challenge (bortezomib LD50 of 30 nM vs 15 nM in U266 overexpressed and control, bortezomib LD50 of 18 nM vs 10 nM in ARH77 overexpressed vs control cells)... Our results demonstrate that elevated PSMC2 and PSMC6 expression correlates with reduced OS in MM. PSMC subunit inactivation decreased proteasome activity and increased dependence on autophagy, while PSMC upregulation increased proteasome activity and reduced PI sensitivity. Proteasome ATPases are actionable targets with a prognostic and therapeutic role in the armamentarium for MM.

PSMC2 is related to the immuno-hot phenotype and predicts the outcome of immunotherapy. Therefore, the current study emphasizes that cancer patients with high PMSC2 expression should actively receive immunotherapy to improve their prognosis.