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Aurora A kinase Inhibition Reprograms Metabolism dependent on PGC1α to Drive Synthetic Lethality with Fatty Acid Oxidation Inhibition in Glioblastoma [ChIP-Seq]

ABSTRACT: By integration of transcriptome, CHIP-seq, ATAC-seq, proteomic and metabolite screening followed by carbon tracing (U-13C-Glucose, U-13C-Glutamine and U-13C-Palmitic acid) and extracellular flux analysis we provided evidence that genetic (shRNA and CRISPR/Cas9) and pharmacological (Alisertib) AURKA inhibition elicited substantial metabolic reprogramming supported in part by inhibition of MYC targets and concomitant activation of PPARA signaling. While glycolysis was suppressed by AURKA inhibition, we noted a compensatory increase in oxygen consumption rate fueled by enhanced fatty acid oxidation (FAO). Whereas interference with AURKA elicited a suppression of c-Myc, we detected an upregulation of PGC1α, a master regulator of oxidative metabolism, upon AURKA inhibition. Chromatin immunoprecipitation experiments confirmed binding of c-Myc to the promoter region of PGC1α, which is abrogated by AURKA inhibition and in turn unleashed PGC1α expression. To interfere with this oxidative metabolic reprogramming, we combined AURKA inhibitors with inhibitors of FAO (etomoxir) and electron transport chain (gamitrinib) and found substantial synergistic growth inhibition in patient derived xenograft in vitro and extension of overall survival without induction of toxicity in normal tissue.

ORGANISM(S): Homo sapiens

PROVIDER: GSE161573 | GEO | 2021/06/01

REPOSITORIES: GEO

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Aurora A kinase Inhibition Reprograms Metabolism dependent on PGC1α to Drive Synthetic Lethality with Fatty Acid Oxidation Inhibition in Glioblastoma [ATAC-Seq]

Project description:By integration of transcriptome, CHIP-seq, ATAC-seq, proteomic and metabolite screening followed by carbon tracing (U-13C-Glucose, U-13C-Glutamine and U-13C-Palmitic acid) and extracellular flux analysis we provided evidence that genetic (shRNA and CRISPR/Cas9) and pharmacological (Alisertib) AURKA inhibition elicited substantial metabolic reprogramming supported in part by inhibition of MYC targets and concomitant activation of PPARA signaling. While glycolysis was suppressed by AURKA inhibition, we noted a compensatory increase in oxygen consumption rate fueled by enhanced fatty acid oxidation (FAO). Whereas interference with AURKA elicited a suppression of c-Myc, we detected an upregulation of PGC1α, a master regulator of oxidative metabolism, upon AURKA inhibition. Chromatin immunoprecipitation experiments confirmed binding of c-Myc to the promoter region of PGC1α, which is abrogated by AURKA inhibition and in turn unleashed PGC1α expression. To interfere with this oxidative metabolic reprogramming, we combined AURKA inhibitors with inhibitors of FAO (etomoxir) and electron transport chain (gamitrinib) and found substantial synergistic growth inhibition in patient derived xenograft in vitro and extension of overall survival without induction of toxicity in normal tissue.

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MET Inhibition Elicits PGC1α Dependent Metabolic Reprogramming in Glioblastoma

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AURKA Inhibition Reprograms Metabolism dependent on PGC1α to Drive Synthetic Lethality with Fatty Acid Oxidation Inhibition in Glioblastoma

Project description:We described the metabolic alterations in glioblastoma model systems elicited by AURKA inhibition. By utilizing proteomic and transcriptomic analyses coupled with untargeted polar and nonpolar metabolite analysis by LC/MC, we found that AURKA inhibition leads to a profound reprogramming of tumor metabolism, which suppresses c-Myc protein levels and increases pro-survival PGC1α which in concert mediate a suppression of glycolysis and a concomitant activation of oxidative phosphorylation (OXPHOS) that is fueled by enhanced fatty acid oxidation (FAO). We targeted these metabolic aberrations with novel combination therapies involving clinical approved drugs in glioblastoma system both in vitro and in vivo. We used microarrays to detail the global programme of gene expression underlying cellularisation and identified distinct classes of up-regulated and down-regulated genes in Alisertib resistant cells.

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Loss of function of CDK7 is Synthetically Lethal with Fatty Acid Oxidation Inhibition in Glioblastoma

Project description:CDK7 has been identified as a potential drug target for glioblastoma (GBM), a highly lethal primary brain tumor. However, resistance to therapy develops quickly, which may be facilitated by drug-induced reprogramming of metabolism. By combination of a transcriptome and metabolite screening analyses followed by carbon tracing (U-13C-Glucose, U-13C-Glutamine and U-13C-Palmitic acid) and extracellular flux analysis, we demonstrated that both genetic and pharmacological (YKL-5-124 and THZ1) CDK7 inhibition elicited substantial metabolic reprogramming. Specifically, CDK7 inhibition elicited an increase of oxygen consumption rate fueled by enhanced fatty acid oxidation (FAO) manifested by enhanced labeling of citric acid cycle intermediates from palmitic acid. Consistently, the combination treatment of CDK7 inhibitors with blockers of FAO (etomoxir) exerted substantial synergistic growth inhibition in patient derived xenograft as well as neurosphere GBM cultures, which was mainly driven by a collapse of oxidative energy metabolism. In turn, exogenous administration of adenosine triphosphate partially rescued from the cell death induced by the combination treatment. Finally, the combined administration of YKL-5-124 and etomoxir extended overall in an orthotopic patient-derived xenograft model of GBM. In summary, these data support that simultaneous targeting of CDK7 and FAO might be a potential novel therapy against GBM.

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AURKA Inhibition Reprograms Metabolism dependent on PGC1α to Drive Synthetic Lethality with Fatty Acid Oxidation Inhibition in Glioblastoma

Project description:AURKA Inhibition Reprograms Metabolism dependent on PGC1α to Drive Synthetic Lethality with Fatty Acid Oxidation Inhibition in Glioblastoma

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MET Inhibition Elicits PGC1α Dependent Metabolic Reprogramming in Glioblastoma

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Tumor metastasis to lymph node requires YAP-dependent metabolic adaptation

Project description:In cancer patients, metastasis of tumors to sentinel lymph nodes (LN) predicts disease progression and often guides treatment decisions. The mechanisms underlying tumor LN metastasis are poorly understood. Using comparative transcriptomics and metabolomics analyses of primary and LN metastatic tumors in mice, we found that LN metastasis requires that tumor cells undergo a metabolic shift toward fatty acid oxidation (FAO). Transcriptional co-activator yes-associated protein (YAP) is selectively activated in LN metastatic tumors, leading to upregulation of genes in the FAO signaling pathway. Pharmacological inhibition of FAO or genetic ablation of YAP suppressed LN metastasis in mice. Several bioactive bile acids were highly accumulated in the LN metastatic tumor. Inhibition of FAO or YAP may merit exploration as therapeutic strategies for mitigating tumor LN metastasis.

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Inhibition of Collagen XI alpha 1–induced Fatty Acid Oxidation Triggers Apoptotic Cell Death in Cisplatin-Resistant Ovarian Cancer

Project description:Collagen type XI alpha 1 (COL11A1) is a novel biomarker associated with cisplatin resistance in ovarian cancer. However, the mechanisms underlying how COL11A1 confers cisplatin resistance in ovarian cancer are poorly understood. We identified that fatty acid β-oxidation (FAO) is upregulated by COL11A1 in ovarian cancer cells and that COL11A1-driven cisplatin resistance can be abrogated by inhibition of FAO. Furthermore, our results demonstrate that COL11A1 also enhances the expression of proteins involved in fatty acid synthesis. Interestingly, COL11A1-induced upregulation of fatty acid synthesis and FAO is modulated by the same signaling molecules. We identified that binding of COL11A1 to its receptors, α1β1 integrin and discoidin domain receptor 2 (DDR2), activates Src-Akt-AMPK signaling to increase the expression of both fatty acid synthesis and oxidation enzymes, although DDR2 seems to be the predominant receptor. Inhibition of fatty acid synthesis downregulates FAO despite the presence of COL11A1, suggesting that fatty acid synthesis might be a driver of FAO in ovarian cancer cells. Taken together, our results suggest that COL11A1 upregulates fatty acid metabolism in ovarian cancer cells in a DDR2-Src-Akt-AMPK dependent manner. Therefore, we propose that blocking FAO might serve as a promising therapeutic target to treat ovarian cancer, particularly cisplatin-resistant recurrent ovarian cancers which typically express high levels of COL11A1.

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