TRAP1, a mitochondrial Hsp90 paralog, maintains stem characteristics of glioma stem cells Hye-Kyung Park1 and Byoung Heon Kang1* 1Department of Biological Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan, South Korea, 44919
Glioblastoma multiforme (GBM) is the most prevalent malignant brain tumor and one of the most resistant tumors to radiation and cytotoxic chemotherapy. Treatment is difficult for these reasons and the relapse rate is very high. Small subpopulation of self-renewing tumor cells, i.e. cancer stem cells (CSCs) or tumor-initiating cells, has been isolated from GBM patients and reported to be responsible for the resistance to therapies and the tumor relapse. Thus, targeting GSCs may provide promising therapeutic approach against the aggressive tumors and overcome relapse after treatment. Cancer cells depend much more on aerobic glycolysis rather than mitochondrial respiration, a phenomenon termed as the Warburg effect, which redirects metabolites for biosynthetic pathways and reduces toxic ROS production. However, the metabolic properties of GSC is controversial so far. In this study, we found the metabolic properties of high mitochondrial respiration and low ROS production were crucial for maintenance of the self-renewal and stemness properties. Furthermore, these metabolic features were critically dependent on the chaperone function of tumor necrosis factor receptor associated protein 1 (TRAP1). TRAP1 is a mitochondrial paralog of the 90 kDa heat shock protein (Hsp90) and is often highly elevated in a variety of cancer cells. Although TRAP1 is involved in mitochondrial permeability transition and drug resistance in cancer cells by regulating cell death threshold, the molecular mechanism is not clearly understood yet due to absence of client protein information. Our results demonstrate that TRAP1 inhibition leads to loss stem cell properties to eventually suppress sphere formation in vitro and tumor growth in vivo and implicate a promising anticancer therapy against GSCs.
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