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Dual inhibition of CPT1A and G6PD suppresses glioblastoma tumorspheres

 Seo Jin Kim  ;  Soo Jeong Park  ;  Junseong Park  ;  Hye Joung Cho  ;  Jin-Kyoung Shim  ;  Jieun Seon  ;  Ran Joo Choi  ;  Seon-Jin Yoon  ;  Ju Hyung Moon  ;  Eui Hyun Kim  ;  Eui Kyo Seo  ;  Sun Ho Kim  ;  Hyun Sil Kim  ;  Wan-Yee Teo  ;  Jong Hee Chang  ;  Jong In Yook  ;  Seok-Gu Kang 
 JOURNAL OF NEURO-ONCOLOGY, Vol.160(3) : 677-689, 2022-12 
Journal Title
Issue Date
Animals ; Carnitine O-Palmitoyltransferase / antagonists & inhibitors ; Carnitine O-Palmitoyltransferase / genetics ; Carnitine O-Palmitoyltransferase / metabolism ; Cell Line, Tumor ; Dehydroepiandrosterone / therapeutic use ; Glioblastoma* / drug therapy ; Glioblastoma* / genetics ; Glioblastoma* / metabolism ; Glucosephosphate Dehydrogenase / antagonists & inhibitors ; Glucosephosphate Dehydrogenase / genetics ; Glucosephosphate Dehydrogenase / metabolism ; Humans ; Mice ; Neoplastic Stem Cells / drug effects ; Neoplastic Stem Cells / metabolism ; Neoplastic Stem Cells / pathology
Carnitine palmitoyltransferase 1A ; Dehydroepiandrosterone ; Etomoxir ; Glioblastoma ; Glucose-6-phosphate dehydrogenase
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.
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Appears in Collections:
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Neurosurgery (신경외과학교실) > 1. Journal Papers
2. College of Dentistry (치과대학) > Dept. of Oral Pathology (구강병리학교실) > 1. Journal Papers
Yonsei Authors
Kang, Seok Gu(강석구) ORCID logo https://orcid.org/0000-0001-5676-2037
Kim, Sun Ho(김선호) ORCID logo https://orcid.org/0000-0003-0970-3848
Kim, Eui Hyun(김의현) ORCID logo https://orcid.org/0000-0002-2523-7122
Kim, Hyun Sil(김현실) ORCID logo https://orcid.org/0000-0003-3614-1764
Moon, Ju Hyung(문주형)
Park, Junseong(박준성)
Yook, Jong In(육종인) ORCID logo https://orcid.org/0000-0002-7318-6112
Yoon, Seon Jin(윤선진) ORCID logo https://orcid.org/0000-0002-3255-5081
Chang, Jong Hee(장종희) ORCID logo https://orcid.org/0000-0003-1509-9800
Cho, Hyejoung(조혜중)
Choi, Ran Joo(최란주)
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