Activation of mitochondrial lactate uptake by flavone induces apoptosis in human colon cancer cells
Article first published online: 27 SEP 2004
Copyright © 2004 Wiley-Liss, Inc.
Journal of Cellular Physiology
Volume 202, Issue 2, pages 379–390, February 2005
How to Cite
Wenzel, U., Schoberl, K., Lohner, K. and Daniel, H. (2005), Activation of mitochondrial lactate uptake by flavone induces apoptosis in human colon cancer cells. J. Cell. Physiol., 202: 379–390. doi: 10.1002/jcp.20129
- Issue published online: 23 NOV 2004
- Article first published online: 27 SEP 2004
- Manuscript Accepted: 16 APR 2004
- Manuscript Received: 8 JAN 2004
Lactate production from glucose even in the presence of oxygen is a characteristic of cancer cell metabolism and an important feature for tumor progression. Here, we describe that an increased uptake of lactate into mitochondria of HT-29 human colon cancer cells by treatment of cells with the flavonoid flavone is associated with an increased production of mitochondrial superoxide anions and apoptotic cell death. In search of the mitochondrial transporter that could promote enhanced lactate uptake and energetic flow through the electron transport chain, we used fluorescein as a model substrate. Flavone increased fluorescein uptake at pH 7.4 into mitochondria of HT-29 cells almost tenfold while lactate inhibited uptake significantly. Uptake of fluorescein in the absence or presence of flavone was strongly increased by lowering pH from 7.4 to 6.0 and almost abolished by the protonophore carbonyl cyanide m-chlorophenylhydrazone (CCCP). The lactate-sensitive part of fluorescein transport was completely blocked by p-chloromercuribenzenesulfonic acid (pCMBS), a specific inhibitor of the monocarboxylate transporter-1 (MCT-1) that by Western blotting and immunofluorescence was identified in mitochondria of HT-29 cells. Finally, lactate increased and pCMBS inhibited the flavone-induced generation of mitochondrial O radicals and in turn blunted the apoptotic response. In conclusion, our studies provide evidence that flavone reverts the metabolic phenotype of transformed colonocytes towards a phenotype characteristic for normal cells. Transformed colonocytes, however, seem especially vulnerable to O, produced in mitochondria as a consequence of these metabolic alterations, and respond with the induction of apoptosis. © 2004 Wiley-Liss, Inc.