| dc.contributor |
Ministerio de Ciencia y Tecnología (España) |
|
| dc.contributor |
Ministerio de Sanidad y Consumo (España) |
|
| dc.contributor |
Fundación Ramón Areces |
|
| dc.creator |
Santamaría, Gema |
|
| dc.creator |
Martínez-Díez, Marta |
|
| dc.creator |
Fabregat, Isabel |
|
| dc.creator |
Cuezva, José M. |
|
| dc.date |
2008-06-05T15:09:49Z |
|
| dc.date |
2008-06-05T15:09:49Z |
|
| dc.date |
2005-12-16 |
|
| dc.date.accessioned |
2017-01-31T01:34:55Z |
|
| dc.date.available |
2017-01-31T01:34:55Z |
|
| dc.identifier |
Carcinogenesis 2006 27(5):925-935 |
|
| dc.identifier |
0305-1048 (Print) |
|
| dc.identifier |
1460-2180 (Online) |
|
| dc.identifier |
http://hdl.handle.net/10261/4825 |
|
| dc.identifier.uri |
http://dspace.mediu.edu.my:8181/xmlui/handle/10261/4825 |
|
| dc.description |
This is a pre-copy-editing, author-produced PDF of an article accepted for publication in Carcinogenesis following peer review. The definitive publisher-authenticated version Carcinogenesis 2006 27(5):925-935 is available at: http://dx.doi.org/10.1093/carcin/bgi315 |
|
| dc.description |
There is a large body of clinical data documenting that most human carcinomas contain reduced levels of the catalytic subunit of the mitochondrial H+-ATP synthase. In colon and lung cancer this alteration correlates with a poor patient prognosis. Furthermore, recent findings in colon cancer cells indicate that downregulation of the H+-ATP synthase is linked to the resistance of the cells to chemotherapy. However, the mechanism by which the H+-ATP synthase participates in cancer progression is unknown. In this work, we show that inhibitors of the H+-ATP synthase delay staurosporine (STS)-induced cell death in liver cells that are dependent on oxidative phosphorylation for energy provision whereas it has no effect on glycolytic cells. Efficient execution of cell death requires the generation of reactive oxygen species (ROS) controlled by the activity of the H+-ATP synthase in a process that is concurrent with the rapid disorganization of the cellular mitochondrial network. The generation of ROS after STS treatment is highly dependent on the mitochondrial membrane potential and most likely caused by reverse electron flow to Complex I. The generated ROS promote the carbonylation and covalent modification of cellular and mitochondrial proteins. Inhibition of the activity of the H+-ATP synthase blunted ROS production prevented the oxidation of cellular proteins and the modification of mitochondrial proteins delaying the release of cytochrome c and the execution of cell death. The results in this work establish the downregulation of the H+-ATP synthase, and thus of oxidative phosphorylation, as part of the molecular strategy adapted by cancer cells to avoid ROS-mediated cell death. Furthermore, the results provide a mechanistic explanation to understand chemotherapeutic resistance of cancer cells that rely on glycolysis as the main energy provision pathway. |
|
| dc.description |
G.S. and M.M-D.
were supported by pre-doctoral fellowships from the Ministerio de Ciencia y
Tecnología. This work was supported by grants from the Ministerio de Sanidad y
Consumo (PI041255), Comunidad de Madrid (SAL/0026/2004) and Ministerio de
Ciencia y Tecnología (BMC2001-0710). The CBMSO receives an institutional grant
from Fundación Ramón Areces. |
|
| dc.description |
Peer reviewed |
|
| dc.format |
982664 bytes |
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| dc.format |
application/pdf |
|
| dc.language |
eng |
|
| dc.publisher |
Oxford University Press |
|
| dc.rights |
openAccess |
|
| dc.subject |
H+-ATP synthase |
|
| dc.title |
Efficient execution of cell death in non-glycolytic cells requires the generation of ROS controlled by the activity of mitochondrial H+-ATP synthase |
|
| dc.type |
Artículo |
|