PMID- 36396930 OWN - NLM STAT- MEDLINE DCOM- 20230110 LR - 20230110 IS - 1573-7373 (Electronic) IS - 0167-594X (Linking) VI - 160 IP - 3 DP - 2022 Dec TI - Dual inhibition of CPT1A and G6PD suppresses glioblastoma tumorspheres. PG - 677-689 LID - 10.1007/s11060-022-04189-z [doi] AB - PURPOSE: Limited treatment options are currently available for glioblastoma (GBM), an extremely lethal type of brain cancer. For a variety of tumor types, bioenergetic deprivation through inhibition of cancer-specific metabolic pathways has proven to be an effective therapeutic strategy. Here, we evaluated the therapeutic effects and underlying mechanisms of dual inhibition of carnitine palmitoyltransferase 1A (CPT1A) and glucose-6-phosphate dehydrogenase (G6PD) critical for fatty acid oxidation (FAO) and the pentose phosphate pathway (PPP), respectively, against GBM tumorspheres (TSs). METHODS: Therapeutic efficacy against GBM TSs was determined by assessing cell viability, neurosphere formation, and 3D invasion. Liquid chromatography-mass spectrometry (LC-MS) and RNA sequencing were employed for metabolite and gene expression profiling, respectively. Anticancer efficacy in vivo was examined using an orthotopic xenograft model. RESULTS: CPT1A and G6PD were highly expressed in GBM tumor tissues. Notably, siRNA-mediated knockdown of both genes led to reduced viability, ATP levels, and expression of genes associated with stemness and invasiveness. Similar results were obtained upon combined treatment with etomoxir and dehydroepiandrosterone (DHEA). Transcriptome analyses further confirmed these results. Data from LC-MS analysis showed that this treatment regimen induced a considerable reduction in the levels of metabolites associated with the TCA cycle and PPP. Additionally, the combination of etomoxir and DHEA inhibited tumor growth and extended survival in orthotopic xenograft model mice. CONCLUSION: Our collective findings support the utility of dual suppression of CPT1A and G6PD with selective inhibitors, etomoxir and DHEA, as an efficacious therapeutic approach for GBM. CI - (c) 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature. FAU - Kim, Seo Jin AU - Kim SJ AD - Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea. AD - Brain Tumor Translational Research Laboratory, Severance Biomedical Research Institute, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea. FAU - Park, Soo Jeong AU - Park SJ AD - Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea. AD - Department of Neurosurgery, Ewha Womans University Seoul Hospital, Ewha Womans University College of Medicine, Seoul, Republic of Korea. FAU - Park, Junseong AU - Park J AD - Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea. AD - Precision Medicine Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea. FAU - Cho, Hye Joung AU - Cho HJ AD - Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea. AD - Brain Tumor Translational Research Laboratory, Severance Biomedical Research Institute, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea. FAU - Shim, Jin-Kyoung AU - Shim JK AD - Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea. AD - Brain Tumor Translational Research Laboratory, Severance Biomedical Research Institute, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea. FAU - Seon, Jieun AU - Seon J AD - Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea. AD - Brain Tumor Translational Research Laboratory, Severance Biomedical Research Institute, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea. FAU - Choi, Ran Joo AU - Choi RJ AD - Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea. AD - Brain Tumor Translational Research Laboratory, Severance Biomedical Research Institute, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea. FAU - Yoon, Seon-Jin AU - Yoon SJ AD - Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea. AD - Brain Tumor Translational Research Laboratory, Severance Biomedical Research Institute, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea. FAU - Moon, Ju Hyung AU - Moon JH AD - Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea. FAU - Kim, Eui Hyun AU - Kim EH AD - Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea. FAU - Seo, Eui Kyo AU - Seo EK AD - Department of Neurosurgery, Ewha Womans University Seoul Hospital, Ewha Womans University College of Medicine, Seoul, Republic of Korea. FAU - Kim, Sun Ho AU - Kim SH AD - Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea. AD - Department of Neurosurgery, Ewha Womans University Seoul Hospital, Ewha Womans University College of Medicine, Seoul, Republic of Korea. FAU - Kim, Hyun Sil AU - Kim HS AD - Department of Oral Pathology, Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul, Republic of Korea. FAU - Teo, Wan-Yee AU - Teo WY AD - Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore, Singapore. AD - Institute of Molecular and Cell Biology, A*STAR, Singapore, Singapore. FAU - Chang, Jong Hee AU - Chang JH AD - Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea. FAU - Yook, Jong In AU - Yook JI AD - Department of Oral Pathology, Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul, Republic of Korea. FAU - Kang, Seok-Gu AU - Kang SG AD - Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea. seokgu9@yuhs.ac. AD - Brain Tumor Translational Research Laboratory, Severance Biomedical Research Institute, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea. seokgu9@yuhs.ac. AD - Department of Medical Science, Yonsei University Graduate School, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea. seokgu9@yuhs.ac. LA - eng GR - NRF-2022R1A2B5B03001199/National Research Foundation of Korea/ GR - 6-2022-0147/Yonsei University College of Medicine/ GR - 6-2021-0217/Yonsei University/ PT - Journal Article DEP - 20221117 PL - United States TA - J Neurooncol JT - Journal of neuro-oncology JID - 8309335 RN - EC 2.3.1.21 (Carnitine O-Palmitoyltransferase) RN - 459AG36T1B (Dehydroepiandrosterone) RN - MSB3DD2XP6 (etomoxir) RN - EC 1.1.1.49 (Glucosephosphate Dehydrogenase) SB - IM MH - Animals MH - Humans MH - Mice MH - Carnitine O-Palmitoyltransferase/antagonists & inhibitors/genetics/metabolism MH - Cell Line, Tumor MH - Dehydroepiandrosterone/therapeutic use MH - *Glioblastoma/drug therapy/genetics/metabolism MH - Glucosephosphate Dehydrogenase/antagonists & inhibitors/genetics/metabolism MH - Neoplastic Stem Cells/drug effects/metabolism/pathology OTO - NOTNLM OT - Carnitine palmitoyltransferase 1A OT - Dehydroepiandrosterone OT - Etomoxir OT - Glioblastoma OT - Glucose-6-phosphate dehydrogenase EDAT- 2022/11/18 06:00 MHDA- 2022/12/21 06:00 CRDT- 2022/11/17 23:53 PHST- 2022/09/26 00:00 [received] PHST- 2022/11/01 00:00 [accepted] PHST- 2022/11/18 06:00 [pubmed] PHST- 2022/12/21 06:00 [medline] PHST- 2022/11/17 23:53 [entrez] AID - 10.1007/s11060-022-04189-z [pii] AID - 10.1007/s11060-022-04189-z [doi] PST - ppublish SO - J Neurooncol. 2022 Dec;160(3):677-689. doi: 10.1007/s11060-022-04189-z. Epub 2022 Nov 17.