Tài liệu Báo cáo khoa học: Pyruvate reduces DNA damage during hypoxia and after reoxygenation in

Pyruvate reduces DNA damage during hypoxia and after

reoxygenation in hepatocellular carcinoma cells

3Emilie Roudier*, Christine Bachelet and Anne Perrin

Unite´ de Biophysique Cellulaire et Mole´ culaire, IFR ‘RMN biome´dicale: de la cellule a` l’homme’, CRSSA, BP 87, La Tronche, France

Pyruvate, as well as lactate, is an end-product of gly￾colysis. Its production is enhanced in tumor cells,

where high rates of aerobic glycolysis, historically

known as the Warburg effect, are observed [1]. It is

only lately that pyruvate has been described as playing

an important role in cancer progression. First of all,

alterations in components of pyruvate metabolism

have been reported in tumor cells, and appeared to

increase cancer cell proliferation [2,3]. Moreover,

recent evidence supports a novel role of pyruvate in

metabolic signaling in tumors. Pyruvate has been

reported to promote hypoxia-inducible factor (HIF-1)

stability and activate HIF-1-inducible gene expression.

This can promote the malignant transformation and

survival of cancer cells [4,5]. Pyruvate also exhibits

strong angiogenic activity in vitro and in vivo and

positively affects angiogenic processes [6]. As the

angiogenic switch is a crucial event in tumorigenesis,

pyruvate may be important for cancer progression. All

together, these findings suggest that pyruvate could

induce the molecular signaling usually caused by

hypoxia.

Chronic or transient hypoxia in the tumor is induced

by heterogeneous bloodflow resulting from impaired

vascularization [7]. Tumor cells are often exposed to

shorter or longer periods of hypoxia or ischemia fol￾lowed by reoxygenation or recirculation. An adaptive

response of cancer cells takes place through multi￾faceted changes [8], which are mainly coordinated by

HIF-1 [9]. The outcome is clonal selection of the

tumor cells that are most resistant and well adapted to

hypoxia [10]. Many alterations occur that induce

Keywords

DNA damage; glutathione; hypoxia;

pyruvate; reoxygenation

Correspondence

A. Perrin, CRSSA ⁄ RBP, Unite´ de

biophysique cellulaire et mole´ culaire, 24

Avenue des Maquis du Gre´ sivaudan, BP 87,

38702 La Tronche Cedex, France

2 Fax ⁄ Tel: + 33 4 76 63 68 79

E-mail: [email protected]

*Present address

De´partement de kine´ siologie, Universite´ de

Montre´ al, Canada

(Received 5 July 2007, revised 10 August

2007, accepted 14 August 2007)

doi:10.1111/j.1742-4658.2007.06044.x

Pyruvate is located at a crucial crossroad of cellular metabolism between

the aerobic and anaerobic pathways. Modulation of the fate of pyruvate,

in one direction or another, can be important for adaptative response to

hypoxia followed by reoxygenation. This could alter functioning of the

antioxidant system and have protective effects against DNA damage

induced by such stress. Transient hypoxia and alterations of pyruvate

metabolism are observed in tumors. This could be advantageous for cancer

cells in such stressful conditions. However, the effect of pyruvate in tumor

cells is poorly documented during hypoxia ⁄reoxygenation. In this study, we

showed that cells had a greater need for pyruvate during hypoxia. Pyruvate

decreased the number of DNA breaks, and might favor DNA repair. We

demonstrated that pyruvate was a precursor for the biosynthesis of gluta￾thione through oxidative metabolism in HepG2 cells. Therefore, gluta￾thione decreased during hypoxia, but was restored after reoxygenation.

Pyruvate had beneficial effects on glutathione depletion and DNA breaks

induced after reoxygenation. Our results provide more evidence that the

a-keto acid promotes the adaptive response to hypoxia followed by reoxy￾genation. Pyruvate might thus help to protect cancer cells under such

stressful conditions, which might be harmful for patients with tumors.

Abbreviations

GSH(c-glutamyl), c-glutamyl glutathione; HIF-1, hypoxia-inducible factor; PCA, perchloric acid; ROS, reactive oxygen species.

15188 FEBS Journal 274 (2007) 5188–5198 Journal compilation ª 2007 FEBS. No claim to original French government works