The Role of Mitochondria in Alveolar Rhabdomyosarcoma
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Rhabdomyosarcoma (RMS) is the third most common type of solid tumors in children. The two main subtypes of RMS widely studied are embryonal RMS (eRMS) and alveolar RMS (aRMS). aRMS is characterized to have a more aggressive phenotype and has been resistant to therapy. The main driver of this aggressiveness has been attributed to the presence of a fusion protein PAX3-FOXO1 formed as a result of translocation of PAX3 and FOXO1 genes between chromosome 2 and 13 which is reported to be found in ~75% of aRMS patients. Current therapies used for aRMS are very limited and drugs used are highly cytotoxic. Most of the patients with aRMS have a very low five-year survival rate when compared to eRMS patients and they undergo a highly rigorous treatment regime, which includes surgery, chemotherapy and radiation therapy. Therefore, there arises a need to develop a less toxic and targeted treatment regime for aRMS patients for their better survival. In the present study, we observed that in aRMS cells, there is an enhanced production of mitochondrial reactive oxygen species (ROS) compared to eRMS cells due to defective oxidative phosphorylation (OXPHOS)-complexes II and III but not complex I of the electron transport chain. High levels of mitochondrial ROS can oxidize macro molecules including proteins, which either leads to their unfolding or interfere with their proper folding, thereby, leading to induction of unfolded protein response (UPR). Therefore, the presence of persistent mitochondrial ROS aRMS cells requires high expression of HSP60, a mitochondrial chaperonin, for proper folding of proteins and maintaining mitochondrial homeostasis. Hence, we hypothesized that inhibition of mitochondrial chaperonin HSP60 by mizoribine, a specific HSP60 ATPase activity inhibitor, should hamper the homeostasis leading to mitochondrial unfolded protein response and since there is no salvage pathway in terms of mitochondrial chaperones, aRMS cells will be primed to death due to enhanced load of unfolded proteins. Indeed, our data showed that pre-treatment of aRMS with mizoribine followed by vincristine, even at very low doses, caused more cell death compared to vincristine alone as evident by trypan blue exclusion assay and caspase-3 activity. Taken together, our data indicate that targeting HSP60 could be a successful therapeutic approach for aRMS because it allows for a reduction in vincristine dose during combination therapy, which is less toxic to the normal cells, and the combination therapy is more efficient in killing cancer cells than vincristine alone.