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Activation of LXR? Inhibits Tumor Respiration and is Synthetically Lethal with Bcl-xL Inhibition

ABSTRACT: Liver-X-receptor agonists (LXR) are known to bear anti-tumor activity. However, their efficacy is limited and additional insights regarding the underlying mechanism are necessary. By performing transcriptome analysis coupled with global polar metabolite screening, we show that LXR agonists, LXR623 and GW3965, enhance synergistically the anti-proliferative effects of BH3-mimetics in solid tumor malignancies. Extracellular flux analysis and carbon tracing experiments (U-13C-Glucose and U-13C-Glutamine) reveal that within 5h activation of LXRb results in reprogramming of tumor cell metabolism, leading to suppression of mitochondrial respiration, a phenomenon not observed in normal human astrocytes. LXR activation elicits a suppression of respiratory complexes at the protein level by reducing their stability. In turn, energy starvation drives an integrated stress response (ISR) that up-regulates pro-apoptotic Noxa in an ATF4 dependent manner. In conventional and patient-derived xenograft models of colon carcinoma, melanoma and glioblastoma, the combination treatment of ABT263 and LXR agonists reduces tumor sizes significantly stronger than single treatments. Therefore, the combination treatment of LXR agonists and BH3-mimetics might be a viable efficacious treatment approach for solid malignancies.

SUBMITTER: Dr. Trang Nguyen

PROVIDER: S-SCDT-EMM-2019-10769 | biostudies-other |

REPOSITORIES: biostudies-other

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Project description:ABT-737 is a pharmacological inhibitor of the anti-apoptotic activity of B-cell lymphoma-extra large (Bcl-xL) protein; it promotes apoptosis of cancer cells by occupying the BH3-binding pocket. We have shown previously that ABT-737 lowers cell metabolic efficiency by inhibiting ATP synthase activity. However, we also found that ABT-737 protects rodent brain from ischemic injury in vivo by inhibiting formation of the pro-apoptotic, cleaved form of Bcl-xL, ?N-Bcl-xL. We now report that a high concentration of ABT-737 (1??M), or a more selective Bcl-xL inhibitor WEHI-539 (5??M) enhances glutamate-induced neurotoxicity while a low concentration of ABT-737 (10?nM) or WEHI-539 (10?nM) is neuroprotective. High ABT-737 markedly increased ?N-Bcl-xL formation, aggravated glutamate-induced death and resulted in the loss of mitochondrial membrane potential and decline in ATP production. Although the usual cause of death by ABT-737 is thought to be related to activation of Bax at the outer mitochondrial membrane due to sequestration of Bcl-xL, we now find that low ABT-737 not only prevents Bax activation, but it also inhibits the decline in mitochondrial potential produced by glutamate toxicity or by direct application of ?N-Bcl-xL to mitochondria. Loss of mitochondrial inner membrane potential is also prevented by cyclosporine A, implicating the mitochondrial permeability transition pore in death aggravated by ?N-Bcl-xL. In keeping with this, we find that glutamate/?N-Bcl-xL-induced neuronal death is attenuated by depletion of the ATP synthase c-subunit. C-subunit depletion prevented depolarization of mitochondrial membranes in ?N-Bcl-xL expressing cells and substantially prevented the morphological change in neurites associated with glutamate/?N-Bcl-xL insult. Our findings suggest that low ABT-737 or WEHI-539 promotes survival during glutamate toxicity by preventing the effect of ?N-Bcl-xL on mitochondrial inner membrane depolarization, highlighting ?N-Bcl-xL as an important therapeutic target in injured brain.

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Activation of LXR? Inhibits Tumor Respiration and is Synthetically Lethal with Bcl-xL Inhibition

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