Activation of mitochondrial lactate uptake by flavone induces apoptosis in human colon cancer cells

被引:39
作者
Wenzel, U [1 ]
Schoberl, K [1 ]
Lohner, K [1 ]
Daniel, H [1 ]
机构
[1] Tech Univ Munich, Mol Nutr Unit, Dept Food & Nutr, D-85350 Freising Weihenstephan, Germany
关键词
D O I
10.1002/jcp.20129
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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-2(-). 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-2(-.), produced in mitochondria as a consequence of these metabolic alterations, and respond with the induction of apoptosis. (C) 2004 Wiley-Liss, lnc.
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收藏
页码:379 / 390
页数:12
相关论文
共 32 条
[1]   BCL-2 PROTECTS FROM OXIDATIVE DAMAGE AND APOPTOTIC CELL-DEATH WITHOUT INTERFERING WITH ACTIVATION OF NF-KAPPA-B BY TNF [J].
ALBRECHT, H ;
TSCHOPP, J ;
JONGENEEL, CV .
FEBS LETTERS, 1994, 351 (01) :45-48
[2]   BCL-2 is involved in preventing oxidant-induced cell death and in decreasing oxygen radical production [J].
Amstad, PA ;
Liu, H ;
Ichimiya, M ;
Berezesky, IK ;
Trump, BF ;
Buhimschi, IA ;
Gutierrez, PL .
REDOX REPORT, 2001, 6 (06) :351-362
[3]   Aerobic glycolysis by proliferating cells: A protective strategy against reactive oxygen species [J].
Brand, KA ;
Hermfisse, U .
FASEB JOURNAL, 1997, 11 (05) :388-395
[4]   Characterization of the high-affinity monocarboxylate transporter MCT2 in Xenopus laevis oocytes [J].
Bröer, S ;
Bröer, A ;
Schneider, HP ;
Stegen, C ;
Halestrap, AP ;
Deitmer, JW .
BIOCHEMICAL JOURNAL, 1999, 341 :529-535
[5]   Lactate shuttles in nature [J].
Brooks, GA .
BIOCHEMICAL SOCIETY TRANSACTIONS, 2002, 30 :258-264
[6]   Role of mitochondrial lactate dehydrogenase and lactate oxidation in the intracellular lactate shuttle [J].
Brooks, GA ;
Dubouchaud, H ;
Brown, M ;
Sicurello, JP ;
Butz, CE .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1999, 96 (03) :1129-1134
[7]   Cardiac and skeletal muscle mitochondria have a monocarboxylate transporter MCT1 [J].
Brooks, GA ;
Brown, MA ;
Butz, CE ;
Sicurello, JP ;
Dubouchaud, H .
JOURNAL OF APPLIED PHYSIOLOGY, 1999, 87 (05) :1713-1718
[8]   Oncogenic alterations of metabolism [J].
Dang, CV ;
Semenza, GL .
TRENDS IN BIOCHEMICAL SCIENCES, 1999, 24 (02) :68-72
[9]   Establishment of human colonic epithelial cells in long-term culture [J].
Deveney, CW ;
RandLuby, L ;
Rutten, MJ ;
Luttropp, CA ;
Fowler, WM ;
Land, J ;
Meichsner, CL ;
Farahmand, M ;
Sheppard, BC ;
Crass, RA ;
Deveney, KE .
JOURNAL OF SURGICAL RESEARCH, 1996, 64 (02) :161-169
[10]   Endurance training, expression, and physiology of LDH, MCT1, and MCT4 in human skeletal muscle [J].
Dubouchaud, H ;
Butterfield, GE ;
Wolfel, EE ;
Bergman, BC ;
Brooks, GA .
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM, 2000, 278 (04) :E571-E579