Dual inhibition of CPT1A and G6PD suppresses glioblastoma tumorspheres

• Published in: Journal of neuro-oncology Vol. 160; no. 3; pp. 677 - 689
• Main Authors: Kim, Seo Jin, Park, Soo Jeong, Park, Junseong, Cho, Hye Joung, Shim, Jin-Kyoung, Seon, Jieun, Choi, Ran Joo, Yoon, Seon-Jin, Moon, Ju Hyung, Kim, Eui Hyun, Seo, Eui Kyo, Kim, Sun Ho, Kim, Hyun Sil, Teo, Wan-Yee, Chang, Jong Hee, Yook, Jong In, Kang, Seok-Gu
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.12.2022; Springer Nature B.V
• Subjects: Animal models; Animals; Brain cancer; Carnitine O-Palmitoyltransferase - antagonists & inhibitors; Carnitine O-Palmitoyltransferase - genetics; Carnitine O-Palmitoyltransferase - metabolism; Carnitine palmitoyltransferase; Cell Line, Tumor; Cell viability; Dehydroepiandrosterone; Dehydroepiandrosterone - therapeutic use; Gene expression; Glioblastoma; Glioblastoma - drug therapy; Glioblastoma - genetics; Glioblastoma - metabolism; Glucosephosphate dehydrogenase; Glucosephosphate Dehydrogenase - antagonists & inhibitors; Glucosephosphate Dehydrogenase - genetics; Glucosephosphate Dehydrogenase - metabolism; Humans; Invasiveness; Liquid chromatography; Mass spectroscopy; Medicine; Medicine & Public Health; Metabolic pathways; Mice; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Neurology; Oncology; Palmitoyltransferase; Pentose phosphate pathway; siRNA; Transcriptomes; Tricarboxylic acid cycle; Tumors; Xenografts; Carnitine palmitoyltransferase 1A; Glucose-6-phosphate dehydrogenase; Dehydroepiandrosterone; Etomoxir; Glioblastoma
• ISSN: 0167-594X; 1573-7373
• DOI: 10.1007/s11060-022-04189-z

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.