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

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)677-689
Number of pages13
JournalJournal of Neuro-Oncology
Volume160
Issue number3
DOIs
StatePublished - Dec 2022

Keywords

  • Carnitine palmitoyltransferase 1A
  • Dehydroepiandrosterone
  • Etomoxir
  • Glioblastoma
  • Glucose-6-phosphate dehydrogenase

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