p53: tumour suppressor or oncogene?

March 22 2008 post: in the past months, I have received more than one message from folks understandably concerned about curcumin’s reported inhibiting effect on what is known as the tumour-suppressor gene, p53. The "Scientific American" article that brought this matter to my attention is listed here on my blog (see “Spice Healer,” here on the right). At first glance, that doesn’t sound good, does it? I mean, that curcumin inhibits a tumour suppressor? Yikes. I was concerned, too. (The image on the left, by the way, shows healthy p53 in its unbound state; the one on the right shows it repairing damaged DNA). I have read conflicting studies on the curcumin-p53 issue, incidentally, which doesn’t help me reach a conclusion.
But a 2005 Science Daily article (http://tinyurl.com/2qg85m) that I read by pure chance recently told me something I did not know about p53. Under normal conditions, very true, p53 exterminates cancer cells. But under conditions of hypoxia (low oxygen), this gene apparently mutates: The less oxygen, the more mutations in the p53 gene, so cancer cells are not killed; instead, they proliferate. Cancer cells proliferate??? Ma scherziamo?
Prof. Kimball’s biology text (see link on my homepage, on the right) informs us that the p53 protein prevents a cell from completing the cell cycle if its DNA is damaged or the cell has suffered other types of damage. When a cell is injured or malfunctioning, in other words, p53 is summoned to assess the situation: if the damage is minor, this gene temporarily halts the cell cycle (cell division); if the damage is major, though, p53 initiates the process of apoptosis. But what happens in the case of a cancer cell?
More than half of human cancers contain p53 mutations and have no functioning p53 protein. And read this: Mice have been cured of cancer by treating them with a peptide that turns on production of the p53 protein in the tumor cells. However, there may be a tradeoff involved: excess production of the p53 protein leads to accelerated aging in mice. The converse appears also to be true: mice expressing high levels of the anti-aging protein Sirt1 have their production of p53 depressed and are more susceptible to cancer.
Damned if you do, damned if you don’t?
The following may help us better understand what is going on. This helpful website (http://tinyurl.com/292n29) provides an overview of p53—its history and structure, how it works and so on. Healthy cells, we are told, have low levels of p53, which can be increased as a result of cell stress or DNA damage. Okay. But while the p53 gene plays an important role in cell cycle control and apoptosis in healthy cells, mutant p53 could allow abnormal cells to proliferate, resulting in cancer. As many as 50% of all human tumors contain p53 mutants (this confirms what Prof. Kimball wrote).
How does the p53 gene gets damaged? Well, by smoking, I read, and also: by mutagens (chemicals, radiation or viruses), increasing the likelihood that the cell will begin uncontrolled division. […] Restoring its function would be a major step in curing many cancers. Okay, I have to read this page more carefully and do some more in depth research.

A May 2007 BBC article (http://tinyurl.com/2sthnc) merely confirms the conflicting nature of p53: a trial at the Georgia Institute of Technology has found chemotherapy patients with normally functioning p53 fare worse than those with mutated p53. This suggests p53 may help some cancers come back. […] If this is the case, a new strategy for fighting cancer might be to develop drugs to disable the functioning of p53 in the tumours of patients undergoing chemotherapy. The lead researcher suggested that p53 may help repair some of the cancer cells damaged by chemotherapy leading to tumour recurrence and explaining the higher mortality rate of patients whose tumours had a functioning p53.

In this scenario, patients are better off with a mutated p53! Extraordinary, when you think about it.

Until recently, I thought p53 was one of the “good guys.” But hey, have a look at this: this research team studied tumour samples from patients with ovarian cancer. Some of the cancer patients had been treated with chemotherapy prior to surgery, and some had not. Only 30% of the chemotherapy patients who had normally functioning p53 were alive five years later, compared to 70% of those with mutated, non-functioning p53. Heckaroni! The full Georgia Institute of Technology study is available online: http://tinyurl.com/2nvajq (I confess, I read only the Discussion part since I need no further convincing). In the image on the right, by the way, the dark stains show the mutated p53 in ovarian cancer cells.
Bottom line: p53 appears to be a cousin of the transcription factor NF-kappaB: as long as cells are normal, both of these transcription factors keep us in good shape. But when cancer begins developing, weird things start happening, and both NF-kappaB and p53 go a bit bonkers. Hmmm, all of this makes me think that perhaps curcumin’s alleged inhibiting effect on p53, if proven to be true!, would not be such a bad thing after all…

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