The bioenergetic signature of cancer

Author: J. M. Cuezva
Submitted: Thursday 10th of February 2011 10:24:29 AM
Submitted by: egf
Language: English
Content type: Learning resource
Educational levels: expert, qc3

Abstract

Cancer is a heterogeneous and complex genetic disease that drives the progressive transformation of normal cells into malignancy by a multistep ordered process. However, and in addition to the contribution of genetic mutations in the well established cancer genes (oncogenes and tumour suppressors), the onset and progression of cancer is also bound to the cancer cell‟s microenvironment and to other epigenetic events that contribute to funnel the cell into malignancy. A change of gear in our understanding of cancer as a disease was provided by the splendid summary of the phenotype of the cancer cell in the following six traits: an unlimited replicative potential, sustained angiogenesis, evasion of apoptosis, self-sufficiency in growth signals, insensitivity to anti-growth signals and tissue invasion and metastasis (1). Certainly, this approach to cancer contrasted the intractable diversity of the genetic alterations found in tumours. Quite recently, the so-called “metabolic reprogramming” of the cancer cell has been added as a seventh hallmark of the cancer phenotype. Otto Warburg, back in the early days of the previous century, made the seminal observation that tumours have an abnormal high rate of aerobic glycolysis and proposed that the bioenergetic activity of mitochondria was impaired in the cancer cell. Warburg‟s hypothesis was largely neglected or considered an epiphenomenon of cell transformation for many years. However, different studies have confirmed that most prevalent carcinomas fulfil Warburg‟s hypothesis. In this presentation I will summarize some of these findings and emphasize its potential translation to the bed-side. The expression level of β-F1-ATPase, which is the catalytic subunit of the mitochondrial H+-ATP synthase, and thus a rate-limiting component of mitochondrial oxidative phosphorylation, inversely correlates with the expression of markers of the glycolytic pathway (GAPDH, PK, etc.) in different human carcinomas. A test to assess the bioenergetic signature in normal and tumour biopsies derived from the same cancer patients, which is a simple protein ratio between two markers of energetic metabolism (β-F1-ATPase/GAPDH ratio) (6), confirmed that a tumour drop in the ratio is a phenotypic trait fulfilled by more than 95% of the carcinomas as assessed in large cohorts of breast, colon and lung cancer patients. These findings suggest a deficit in the overall cellular activity of mitochondria in the cancer cell which is consistent with Warburg‟s postulates. Moreover, the bioenergetic signature further affords an excellent marker of the prognosis of cancer patients and of the tumour response to therapy (2). Clinical data from positron emission tomography (PET) using 2-deoxy-2-[18F]fluoro-D-glucose (FDG) as probe and of the bioenergetic signature of the tumours in lung cancer patients have provided support that an altered oxidative phosphorylation is one of the determinants that underlies the abnormal aerobic glycolysis of the cancer cell. Post-transcriptional regulation by the specific inhibition of the translation of the mRNA that encodes β-F1-ATPase partially explains the abnormal biogenesis of mitochondria in colon, lung and breast cancer patients as well as in rat hepatocarcinomas. In contrast, gene silencing by hypermethylation of the ATP5B promoter explains the down-regulation of β-F1-ATPase expression in chronic myeloid leukaemia (10). Cellular proliferation is bound to the synchronous fluctuation of cycles of an increased glycolysis concurrent with a restrained oxidative phosphorylation. Therefore, the metabolic reprogramming experienced by cancer cells could partially result from the onset of cellular proliferation. To assess the contribution of mitochondrial bioenergetics in cancer progression we have generated colon cancer cell lines that express different levels of β-F1-ATPase. The generated cells exhibit large structural and functional differences in their mitochondria and in their in vivo tumour forming capacity. We have confirmed that the activity of oxidative phosphorylation defines the rate of glucose utilization by aerobic glycolysis. The aggressive cellular phenotype, which is highly glycolytic, is bound to the deregulated expression of genes involved in energetic metabolism (11). Remarkably, the molecular and ultrastructural analysis of the tumours derived from the different cell lines highlighted that tumour promotion inevitably requires the selection of cancer cells with a repressed biogenesis and functional activity of mitochondria, i.e., the highly glycolytic phenotype is selected for tumour development. In others words, cancer cells with a functional bioenergetic activity of mitochondria are unable to promote tumour development. In the same study, we demonstrate that the aggressive phenotype of the cells is a non-genetically acquired condition imposed by the cellular microenvironment. Overall, I will stress that energetic metabolism affords a target to develop new cancer therapies because the activity of mitochondria has an unquestionable tumour suppressor function.

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J. M. Cuezva. The bioenergetic signature of cancer. EUROGENE portal. February 2011. online: http://eurogene.open.ac.uk/content/bioenergetic-signature-cancer

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