Abstract
Brain tumor initiating cells (BTICs) co-opt the neuronal high affinity glucose transporter, GLUT3, to withstand metabolic stress. We investigated another mechanism critical to brain metabolism, mitochondrial morphology, in BTICs. BTIC mitochondria were fragmented relative to non-BTIC tumor cell mitochondria, suggesting that BTICs increase mitochondrial fission. The essential mediator of mitochondrial fission, dynamin-related protein 1 (DRP1), showed activating phosphorylation in BTICs and inhibitory phosphorylation in non-BTIC tumor cells. Targeting DRP1 using RNA interference or pharmacologic inhibition induced BTIC apoptosis and inhibited tumor growth. Downstream, DRP1 activity regulated the essential metabolic stress sensor, AMP-activated protein kinase (AMPK), and targeting AMPK rescued the effects of DRP1 disruption. Cyclin-dependent kinase 5 (CDK5) phosphorylated DRP1 to increase its activity in BTICs, whereas Ca 2+-calmodulin-dependent protein kinase 2 (CAMK2) inhibited DRP1 in non-BTIC tumor cells, suggesting that tumor cell differentiation induces a regulatory switch in mitochondrial morphology. DRP1 activation correlated with poor prognosis in glioblastoma, suggesting that mitochondrial dynamics may represent a therapeutic target for BTICs.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 501-510 |
| Number of pages | 10 |
| Journal | Nature neuroscience |
| Volume | 18 |
| Issue number | 4 |
| DOIs | |
| State | Published - Apr 28 2015 |
Funding
We appreciate flow cytometry assistance from C. Shemo and S. O’Bryant, and the tissue provided by M. McGraw, the Cleveland Clinic Foundation Tissue Procurement Service and A.E. Sloan (University Hospitals). I. Nakano (Ohio State University) kindly provided the IN528 model. We thank members of the Rich laboratory for critical reading of the manuscript and discussions. We thank A. Janocha for help with using the Seahorse XF Extracellular Flux Analyzer. Special thanks to D. Napier for her histologic expertise. Finally, we thank our funding sources: US National Institutes of Health grants CA154130, CA169117, CA171652, NS087913, NS089272 (J.N.R.), and CA155764, 2P20 RR020171 COBRE pilot grant (C.M.H.) and NS070315 (S.B.); the Research Programs Committees of Cleveland Clinic (J.N.R.); and the James S. McDonnell Foundation (J.N.R.). C.M.H. was supported by the Peter and Carmen Lucia Buck Training Program in Translational Clinical Oncology and the University of Kentucky College of Medicine Physician Scientist Program. The Markey Biospecimen and Tissue Procurement (BSTP) Shared Resource Facility facilitated the construction of tissue microarrays and immunohistochemical studies. The BSTP Shared Resource Facility is supported by the University of Kentucky Markey Cancer Center (P30CA177558).
ASJC Scopus subject areas
- General Neuroscience