The bioenergetic signature of cancer: a marker of tumor progression.
Mitochondrial H+-ATP synthase is required for cellular energy provision and for efficient execution of apoptosis. Almost one century ago, Otto Warburg proposed the hypothesis that mitochondrial function might be impaired in cancer cells. However, his hypothesis was never demonstrated in human carcinomas. In this study, we have analyzed the expression of the beta-catalytic subunit of the H+-ATP synthase (beta-F1-ATPase) of mitochondria in carcinomas of the human liver, kidney, and colon. We show that carcinogenesis in the liver involves a depletion of the cellular mitochondrial content, as revealed by reduced content of mitochondrial markers, whereas in kidney and colon carcinomas, it involves a selective repression of the expression of the beta-F1-ATPase concurrent with an increase in the expression of the glycolytic glyceraldehyde-3-phosphate dehydrogenase. Both mechanisms limit mitochondrial cellular activity in cancer, strongly supporting Warburg's hypothesis, and suggest a mechanism for the resistance and compromised apoptotic potential of tumor cells. Furthermore, we show that the metabolic state of the cell, as defined by a bioenergetic mitochondrial index relative to the cellular glycolytic potential, provides a signature of carcinogenesis of prognostic value in assessing the progression of colorectal carcinomas.
Cuezva
José M
JM
Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid-Consejo Superior Investigaciones Científicas, Universidad Autónoma de Madrid, 28049 Madrid, Spain. jmcuezva@cbm.uam.es
Krajewska
Maryla
M
de Heredia
Miguel López
ML
Krajewski
Stanislaw
S
Santamaría
Gema
G
Kim
Hoguen
H
Zapata
Juan M
JM
Marusawa
Hiroyuki
H
Chamorro
Margarita
M
Reed
John C
JC
D000818:Animals; D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000473:pathology; D002384:Catalysis; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000473:pathology; D018450:Disease Progression; D004734:Energy Metabolism; D006801:Humans; D007150:Immunohistochemistry; D007680:Kidney Neoplasms / Q000201:enzymology* / Q000473:pathology; D008113:Liver Neoplasms / Q000201:enzymology* / Q000473:pathology; D008930:Mitochondria, Liver / Q000201:enzymology; D006180:Proton-Translocating ATPases / Q000096:biosynthesis* / Q000378:metabolism; D011817:Rabbits; D051381:Rats
D014408:Biomarkers, Tumor; D006180:Proton-Translocating ATPases