The Mitochondrial Protease LonP1 Promotes Proteasome Inhibitor Resistance in Multiple Myeloma

SIMPLE SUMMARY: Multiple myeloma is the second most common cancer of the blood system in the US. Despite new therapies, a cure remains elusive, and current drugs inevitably become ineffective due to various resistance mechanisms. A frontline clinical strategy is the inhibition of the proteasome, the main cellular machinery that degrades proteins in the cytosol and nucleus. Mitochondria are organelles that contain their own set of proteases for protein degradation. Surprisingly, proteases inside mitochondria are also capable of processing proteins normally found outside of these organelles. In this study, we provide evidence that the mitochondrial protease LonP1 can compensate when the proteasome is inhibited and that increased levels of LonP1 confer partial resistance against proteasome inhibitors in multiple myeloma. ABSTRACT: Multiple myeloma and its precursor plasma cell dyscrasias affect 3% of the elderly population in the US. Proteasome inhibitors are an essential part of several standard drug combinations used to treat this incurable cancer. These drugs interfere with the main pathway of protein degradation and lead to the accumulation of damaged proteins inside cells. Despite promising initial responses, multiple myeloma cells eventually become drug resistant in most patients. The biology behind relapsed/refractory multiple myeloma is complex and poorly understood. Several studies provide evidence that in addition to the proteasome, mitochondrial proteases can also contribute to protein quality control outside of mitochondria. We therefore hypothesized that mitochondrial proteases might counterbalance protein degradation in cancer cells treated with proteasome inhibitors. Using clinical and experimental data, we found that overexpression of the mitochondrial matrix protease LonP1 (Lon Peptidase 1) reduces the efficacy of proteasome inhibitors. Some proteasome inhibitors partially crossinhibit LonP1. However, we show that the resistance effect of LonP1 also occurs when using drugs that do not block this protease, suggesting that LonP1 can compensate for loss of proteasome activity. These results indicate that targeting both the proteasome and mitochondrial proteases such as LonP1 could be beneficial for treatment of multiple myeloma.