EXTH-66. BIOENERGETIC SWITCH AND BIOLOGIC RESPONSE WITH SLC25A11 INHIBITION TARGETING MALATE-ASPARTATE SHUTTLE (MAS) ON GLIOBLASTOMA TUMORSPHERE

Autor: Hejoung Cho, Jihwan Yoo, Ran Joo Choi, Junseong Park, Seon-Jin Yoon, Yoojung Oh, Ju Hyung Moon, Eui Hyun Kim, Jong Hee Chang, Seok-Gu Kang
Rok vydání: 2022
Předmět:
Zdroj: Neuro-Oncology. 24:vii224-vii224
ISSN: 1523-5866
1522-8517
Popis: BACKGROUND: Cancer cells depended on cytosolic nicotinamide adenine dinucleotide (NADH) transported into mitochondria via the malate-aspartate shuttle (MAS) for ATP production. KN612 (N-phenylmaleimide), a MAS inhibitor, is known to interfere with cancer growth by reducing ATP production, supported by several studies except on glioblastoma (GBM). Therefore, this study was designed to elucidate whether MAS could be an aimable target in GBM. METHODS: We compared expression levels of MAS conforming enzymes between normal and GBM samples. Gene expression profiles were analyzed using RNA-sequencing. Mitochondrial activity was measured by oxygen consumption (OCR), tetramethylrhodamine-ethylester (TMRE) staining, and liquid chromatograph-tandem mass spectrometer (LC-MS/MS). Also, biological functions were measured by cell viability, ATP levels, NADH levels, stemness, and invasiveness. In vivo efficacies were confirmed using a mouse orthotopic xenograft model. RESULTS: An analysis of the microarray database revealed that expression levels of several MAS enzymes including OGC (SLC25A11) were elevated in GBM. Through RNA sequencing, it was confirmed that KN612 accurately targeted SLC25A11 and decreased its expression. KN612-treated cells showed decreased viability, ATP production, and NADH levels compared with control cells. Under the same conditions, a significant decrease in stemness, invasion, and MMP was confirmed. In addition, KN612 confirmed remarkable therapeutic responses in a mouse orthotopic xenograft model. CONCLUSION: Our results show that KN612 effectively inhibits cancer cells both at the cellular level and at the in vivo level. This shows that targeting MAS could be a potential treatment option in addition to the currently limited standard GBM therapy.
Databáze: OpenAIRE
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