Abstract
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.
Highlights
Certain tumor types are highly treatment resistant and require additional attention with regards to the design of novel treatments
We found that the simultaneous administration of JQ1 and the mitochondrial matrix chaperone inhibitor, Gamitrinib-TPP, causes enhanced reduction of proliferation in established glioblastoma cells (U87, T98G and LN229), stem cell-like glioma cultures (NCH644) and patient derived xenograft cultures (GBM14 and GBM39) and that this occurred in a statistically significant manner (Figure 1B and 1C)
We discovered a novel synthetic lethal interaction between the inhibition of mitochondrial matrix chaperones and c-myc
Summary
Certain tumor types are highly treatment resistant and require additional attention with regards to the design of novel treatments. We propose a novel treatment strategy for the most common primary brain tumor, glioblastoma [1, 2]. One of the most prominent observations is the reliance of tumor cells on “aerobic glycolysis”. This term was coined by the fact that tumor cells heavily depend on glycolysis despite the abundant presence of oxygen. Instead of metabolizing glucose via the citric acid cycle and subsequent oxidative phosphorylation, tumor cells convert glucose to lactate, producing only a much smaller amount of ATP. This inefficient energy production by tumor cells renders them susceptible to certain treatment strategies
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