Loss of tyrosine catabolic enzyme HPD promotes glutamine anaplerosis through mTOR signaling in liver cancer

Abstract

Highlights d Loss of HPD promotes cell proliferation and hepatic tumorigenesis d HPD silencing promotes glutamine anaplerosis through mTOR activation d Co-targeting p70S6 kinase and glutaminase suppresses hepatic tumors with loss of HPD d Loss of HPD is predictive of the response to combined metabolic therapy

Untargeted plasma metabolomics for risk prediction of hepatocellular carcinoma: A prospective study in two Chinese cohorts

“…A prior study found that gut dysbiosis might lead to the abnormal accumulation of serum phenylalanine and tyrosine, and therefore contribute to liver disease progression, emphasizing the potential role of the gut‐liver axis in the progression of liver disease 39 . Furthermore, the suppression of a tyrosine catabolic enzyme (4‐hydroxyphenylpyruvate dioxygenase) was proposed to account for the disordered tyrosine metabolism that displayed cariogenic potentials in hepatocytes 40 . In vivo evidence also shows that long‐term subcutaneous injection of HPLA in mice can induce tumors of varied histogenesis including liver cancer 41 .…”

“…39 Furthermore, the suppression of a tyrosine catabolic enzyme (4-hydroxyphenylpyruvate dioxygenase) was proposed to account for the disordered tyrosine metabolism that displayed cariogenic potentials in hepatocytes. 40 In vivo evidence also shows that long-term subcutaneous injection of HPLA in mice can induce tumors of varied histogenesis including liver cancer. 41 Consistent with previous functional studies showing the roles of cysteine, methionine, arginine, and glycine in HCC initiation and progression, [41][42][43][44] we found positive associations with cystathionine, 2,3-dihydroxy-5-methylthio-4-pentenoic acid (DMTPA), citrulline, and sarcosine, which are intermediates of the above four amino acids.…”

Protocols to culture and harvest hepatic tumor organoids for metabolic assays

“…We recommend testing the effects at multiple time points. The suggested time points for hepatic tumor organoids are 3, 6 and 9 days ( Tong et al., 2021 ). After incubation at specific time points, dispense 15 μL of CellTiter-Glo® 2.0 Luminescent Cell Viability Assay (CellTiter-Glo solution) into each well, and resuspend the mixture.…”

“…We recommend testing the effects at multiple time points. The suggested time points for hepatic tumor organoids are 3, 6 and 9 days ( Tong et al., 2021 ).…”

“…# represents p<0.05 (single versus combination treatment). For a detailed graphical presentation of the results and the molecular mechanisms involved, please refer to Tong et al. (2021) .…”