Mitochondrial matrix chaperone and c-myc inhibition causes enhanced lethality in glioblastoma
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Chiaki Tsuge Ishida1, Chang Shu1, Marc-Eric Halatsch2, Mike-Andrew Westhoff3, Dario C. Altieri4, Georg Karpel-Massler2, Markus David Siegelin1
1Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA
2Department of Neurosurgery, Ulm University Medical Center, Ulm, Germany
3Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany
4The Wistar Institute, Philadelphia, PA, USA
Keywords: gamitrinib, c-myc, OTX015, JQ1, apoptosis
Received: February 15, 2017 Accepted: March 03, 2017 Published: March 15, 2017
Malignant gliomas display high levels of the transcription factor c-myc and organize a tumor specific chaperone network within mitochondria. Here, we show that c-myc along with mitochondrial chaperone inhibition displays massive tumor cell death. Inhibition of mitochondrial matrix chaperones and c-myc was established by utilizing genetic as well as pharmacological approaches. Bromodomain and extraterminal (BET) family protein inhibitors, JQ1 and OTX015, were used for c-myc inhibition. Gamitrinib was applied to interfere with mitochondrial matrix chaperones. A xenograft model was used to determine the in vivo efficacy. Combined inhibition of c-myc and mitochondrial matrix chaperones led to a synergistic reduction of cellular proliferation (CI values less than 1) in established glioblastoma, patient-derived xenograft and stem cell-like glioma cultures. The combinatorial treatment of BET inhibitors and Gamitrinib elicited massive apoptosis induction with dissipation of mitochondrial membrane potential and activation of caspases. Mechanistically, BET-inhibitors and Gamitrinib mediated a pronounced integrated stress response with a PERK-dependent up regulation of ATF4 and subsequent modulation of Bcl-2 family of proteins with down-regulation of Mcl-1 and its interacting partner, Usp9X, and an increase in pro-apoptotic Noxa. Blocking ATF4 by siRNA attenuated Gamitrinib/BET inhibitor mediated increase of Noxa. Knockdown of Noxa and Bak protected from the combinatorial treatment. Finally, the combination treatment of Gamitrinib and OTX015 led to a significantly stronger reduction of tumor growth as compared to single treatments in a xenograft model of human glioma without induction of toxicity. Thus, Gamitrinib in combination with BET-inhibitors should be considered for the development for clinical application.
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