Targeting Mitochondria for Rhabdomyosarcoma Therapy
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Rhabdomyosarcoma (RMS) is a malignant soft-tissue sarcoma in children, accounting for about 40% of pediatric soft-tissue tumors. The two main subtypes of RMS widely studied are embryonal RMS (eRMS) and alveolar RMS (aRMS). Current therapies include chemotherapy and radiation, which are very limited, highly cytotoxic, and have higher chances of recurrence. Although, survival rates have not significantly improved for past three decades, there have been no substantial changes in the treatment strategies, which points out to the need of the hour to develop new approaches to combat rhabdomyosarcoma. The previous study in our lab suggested that the rhabdomyosarcoma cells produce high levels of mitochondrial reactive oxygen species (mito ROS), and because of defective oxidative phosphorylation complexes, along with high levels of mitochondrial unfolded protein response (mtUPR) components. This study hypothesizes a therapeutic intervention targeting the mtUPR machinery, which would increase the load of unfolded proteins in the cells that would further elevate the oxidative stress, skewing the cells towards apoptosis. For this, we screened a library of small molecules against mitochondrial protease that is a component of mtUPR machinery. The screening results showed one promising small molecule DCEM 2, which we studied further. Our results show that DCEM 2 treatment at micro molar levels increased the oxidative stress, ubiquitinated proteins, and caspase- 3 activation whereas it reduced cell viability in both aRMS and eRMS cells with minimal effect on normal myoblast cells. Moreover, the DCEM 2 treatment drastically reduced the oxygen consumption rate and reduces the aRMS signature fusion protein PAX3- FOXO1 levels. Overall, our data suggest that targeting the mtUPR components would be a promising therapeutic strategy for ROS driven cancers like rhabdomyosarcoma.