New research published in the journal Cancer Cell reveals that the lack or loss of a protein in the cells known as SIRT3, induces the proliferation of this disease, suggesting that this protein may be a therapeutic target in the development of effective therapies for cancer.
The research was led by Dr. Marcia Haigis of Harvard Medical School, with the participation of Dr. Arkaitz Carracedo, from the Proteomics Laboratory at CIC bioGUNE.
One of the grand aims of the scientific community is to identify the characteristics that differentiate normal cells from cancerous ones in order to subsequently develop therapies that wipe out the aberrant cells without affecting the normal ones. One hundred years ago, a researcher named Otto Warburg observed that cancerous cells feed in a singular manner: instead of using nutrients to produce energy, it seems they waste part of the food through a less efficient metabolism. Warburg maintained the hypothesis that cancer cells have an aberrant metabolism, which he attributed to a technical defect in these cells. They did not use food to generate energy (ATP) but to generate biomass and build more cells, divide, proliferate, etc.
"In recent years, we have come to understand this phenomenon better. Paradoxically, the cancer cells obtain sufficient energy from nutrients -- equivalent to the electricity for supplying all the appliances in our house -- while what is limiting for them is material to build more cells or what we can imagine as the bricks to build more houses," explained Dr. Carracedo. "To this end, they modify their metabolism in order to create more of these building blocks (cell membrane, ADN, proteins, and so on). This change in the metabolic behaviour of the tumour cell is known as the Warburg Effect, in honour of the researcher."
With this precedent, it is clear that if the way the metabolism of tumour cells is reprogrammed can be understood, more powerful and specific therapies can be designed. Dr. Haigis's team focused their research on new proteins that regulate the metabolism of the cells and known as Sirtuins, and detected that if a protein of this family of sirtuins (known as SIRT3) were eliminated from the cells, these modified their mode of feeding on and processing of nutrients, showing a remarkable similarity with a cancerous cell.
"We discovered that a loss of SIRT3 triggered the Warburg Effect. SIRT3 acts as a 'guardian' in the cell, ensuring that the metabolic processes function correctly. Nevertheless, with loss of SIRT3, another very important protein for the cell, known as HIF1α and which has to be strictly controlled, goes out of control and alters the metabolism," stated Dr. Carracedo.
According to this hypothesis, a cancerous cell will benefit from the elimination of SIRT3 protein. "We confirmed this idea after observing that cells in mice without SIRT3 generated cancers that developed more," stated Br Carracedo. "These genes are fighting constantly. When we lose the SIRT3 gene, the HIF1α protein increases, it destabilises. This promotes tumour growth."
In order to undertake the most important confirmation -- the extrapolation of data to human beings -- pathology and bioinformatics experts were included in this project. The researchers helped demonstrate that, effectively, many cancers, and principally breast cancer, presented reduced levels of SIRT3, together with signs of altered metabolism. Thus, they arrived at the conclusion that SIRT3 protein is a 'guardian' of the metabolism, and that the design of pharmaceutical drugs for promoting this activation could be of great interest in the treatment of cancer.
- Lydia W.S. Finley, Arkaitz Carracedo, Jaewon Lee, Amanda Souza, Ainara Egia, Jiangwen Zhang, Julie Teruya-Feldstein, Paula I. Moreira, Sandra M. Cardoso, Clary B. Clish, Pier Paolo Pandolfi, Marcia C. Haigis. SIRT3 Opposes Reprogramming of Cancer Cell Metabolism through HIF1α Destabilization. Cancer Cell, 2011; 19 (3): 416 DOI: 10.1016/j.ccr.2011.02.014
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