Continuous pyruvate carbon flux to newly synthesized cholesterol and the suppressed evolution of pyruvate-generated CO 2 in tumors: Further evidence for a persistent truncated Krebs cycle in hepatomas

Abstract

Viable tissue slices from rat liver and Morris hepatoma 3924A were compared as to their ability to incorporate carbons from [U- 14C]pyruvate into newly synthesized cholesterol versus CO 2. By 4 h, the tumor slice incubation had incorporated over 6-fold more pyruvate carbons into the sterol than into CO 2, relative to the normal liver slice incubation, per g tissue protein. However, the presence of the mitochondrial citrate exchange carrier inhibitor 1,2,3-benzenetricarboxylate in the incubation inhibited the formation of [ 14C]cholesterol, while simultaneously leading to an increase in the rate of 14CO 2 production in the tumor. In the normal liver system by contrast, benzenetricarboxylate also inhibited [ 14C]cholesterol formation, but had hardly any effect on the already high rate of 14CO 2 production. The ability of benzenetricarboxylate to inhibit the rapid carbon flux from pyruvate to cholesterol, and to steer the metabolic flow of carbons toward oxidative decarboxylation via the Krebs cycle in whole, viable tumor tissue, indirectly emphasizes the importance of the mitochondrial citrate exchange carrier in supporting the decontrol of cholesterogenesis de novo in tumors by accelerating the supply of lipogenic precursor carbons to the tumor cytosol. These studies may be therefore interpreted as extensions, to the level of whole-cell metabolism, of the concept of a persistent ‘truncated’ Krebs cycle in the mitochondria of metastatic cancer tissue. This concept states, in part, that a rapid efflux of mitochondrially generated citrate would operate preferentially in tumors, and thus provide carbons continuously to the cytoplasmic compartment where the well-established deregulated pathway of cholesterogenesis occurs (Parlo, R.A. and Coleman, P.S. (1984) J. Biol. Chem. 259, 9997–10003; Coleman, P.S. and Lavietes, B.B. (1981) CRC Crit. Rev. Biochem. 11, 341–393).