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Summary Tumors display profound changes in cellular metabolism, yet how these changes aid the development and growth of tumors is not fully understood. Here we use a multi-omic approach to examine liver carcinogenesis and regeneration, and find that progressive loss of branched-chain amino acid (BCAA) catabolism promotes tumor development and growth. In human hepatocellular carcinomas and animal models of liver cancer, suppression of BCAA catabolic enzyme expression led to BCAA accumulation in tumors, though this was not observed in regenerating liver tissues. The degree of enzyme suppression strongly correlated with tumor aggressiveness, and was an independent predictor of clinical outcome. Moreover, modulating BCAA accumulation regulated cancer cell proliferation in vitro, and tumor burden and overall survival in vivo. Dietary BCAA intake in humans also correlated with cancer mortality risk. In summary, loss of BCAA catabolism in tumors confers functional advantages, which could be exploited by therapeutic interventions in certain cancers.

Recent studies have shown that many organophosphates can bind competitively and noncompetitively to membrane muscarinic receptors. The present study investigated the responses of the rat aortic rings to diisopropyl-flurophosphate (DFP), an organophsophorus cholinesterase inhibitor, and the possible involvement of muscarinic receptors. DFP caused a concentration-dependent contraction when added cumulatively from 10 −8 to 10 −4 M. This contraction was inhibited in a noncompetitive manner by high concentrations of atropine (1.5×10 −6 and 1.8×10 −6 M) but was unaffected by similar concentrations of selective muscarinic receptor subtype antagonists, pirenzepine, 11-2[2-[(diethylamino)methyl]-1-piperidinyl]acetyl-5,11-dihydro-6 H -rido[2,3- b ][1,4]benzodiazepin-6-one (AF-DX116) and 4-Diphenylacetoxy- N -methyl piperidine methiodide (4-DAMP). Phentolamine, an α-adrenoceptor antagonist, was able to inhibit the DFP-induced contraction in a noncompetitive manner at a concentration of 10 −7 M. These findings suggested that the DFP-induced contraction in the rat aortic rings was mediated by norepinephrine that was released from sympathetic nerve terminals present in the aortic rings.