4.7 Article

PFKFB3-mediated Pro-glycolytic Shift in Hepatocellular Carcinoma Proliferation

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Publisher

ELSEVIER INC
DOI: 10.1016/j.jcmgh.2022.09.009

Keywords

Aerobic Glycolysis; Hyperpolarized 13C MRI

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This study investigated the glycolytic regulation factors in hepatocellular carcinoma (HCC) and explored their potential therapeutic targets. The results showed that inhibiting PFKFB3 can prevent glycolytic-mediated HCC proliferation, which can be monitored by in vivo h13C MRI.
BACKGROUND & AIMS: Metabolic reprogramming, in partic-ular, glycolytic regulation, supports abnormal survival and growth of hepatocellular carcinoma (HCC) and could serve as a therapeutic target. In this study, we sought to identify glycolytic regulators in HCC that could be inhibited to prevent tumor progression and could also be monitored in vivo, with the goal of providing a theragnostic alternative to existing therapies. METHODS: An orthotopic HCC rat model was used. Tumors were stimulated into a high-proliferation state by use of off -target liver ablation and were compared with lower -proliferating controls. We measured in vivo metabolic alter-ation in tumors before and after stimulation, and between stimulated tumors and control tumors using hyperpolarized 13C magnetic resonance imaging (MRI) (h(13)C MRI). We compared metabolic alterations detected by h(13)C MRI to metabolite levels from ex vivo mass spectrometry, mRNA levels of key glycolytic regulators, and histopathology. RESULTS: Glycolytic lactate flux increased within HCC tumors 3 days after tumor stimulation, correlating positively with tu-mor proliferation as measured with Ki67. This was associated with a shift towards aerobic glycolysis and downregulation of the pentose phosphate pathway detected by mass spectrometry. MRI-measured lactate flux was most closely coupled with PFKFB3 expression and was suppressed with direct inhibition using PFK15. CONCLUSIONS: Inhibition of PFKFB3 prevents glycolytic-mediated HCC proliferation, trackable by in vivo h13C MRI. (Cell Mol Gastroenterol Hepatol 2023;15:61-75; https://doi.org/ 10.1016/j.jcmgh.2022.09.009)

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