1. Department of Pharmaceutical Sciences, Biomanufacturing Research Institute Biotechnology Enterprise (BRITE), North Carolina Central University, 1801 Fayetteville St, Durham, NC, 27707, USA.
2. Department of Biology, University of Wisconsin-La Crosse, 1725 State St, La Crosse, WI, 54601, USA.
3. Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, 27708, USA.
4. Department of Neurology, Neuroscience Center, General Hospital of Ningxia Medical University, and Key Laboratory of Craniocerebral Diseases of Ningxia Hui Autonomous Region, Yinchuan 750004, China.
Mammalian target of rapamycin (mTOR) is upregulated in a high percentage of glioblastomas. While a well-known mTOR inhibitor, rapamycin, has been shown to reduce glioblastoma survival, the role of mitochondria in achieving this therapeutic effect is less well known. Here, we examined mitochondrial dysfunction mechanisms that occur with the suppression of mTOR signaling. We found that, along with increased apoptosis, and a reduction in transformative potential, rapamycin treatment significantly affected mitochondrial health. Specifically, increased production of reactive oxygen species (ROS), depolarization of the mitochondrial membrane potential (MMP), and altered mitochondrial dynamics were observed. Furthermore, we verified the therapeutic potential of rapamycin-induced mitochondrial dysfunction through co-treatment with temzolomide (TMZ), the current standard of care for glioblastoma. Together these results demonstrate that the mitochondria remain a promising target for therapeutic intervention against human glioblastoma and that TMZ and rapamycin have a synergistic effect in suppressing glioblastoma viability, enhancing ROS production, and depolarizing MMP.
Keywords: Rapamycin, glioblastoma, mTOR signaling, mitochondrial dynamics, mitochondrial dysfunction, Temozolomide