Tumour suppressor…helps tumours thrive?

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…

The dual nature of NF-kB

This is the continuation of my January 22 post. From the Aggarwal (et al) NF-kB study, we know that when NF-kB “is found to persist in the nucleus, it is referred to as constitutive activation. […] The precise role of constitutive activation in tumors is not known but has been linked to resistance to apoptosis in human cutaneous T-cell lymphoma cells. It is tempting to believe that a similar mechanism accounts for the progression of all tumors that constitutively express NF-kB, but such a link has yet to be clearly identified.”

This entire section is interesting, actually, since it reports that another thing that has not been identified is the actual stimulus that renders NF-kB active all the time. What is clear, though, is that “Cells that express constitutively activated NF-kB are resistant to various chemotherapeutic agents and radiation treatment.”

And read this. In renal cell carcinoma (RCC) patients, “Serum C-reactive protein (CRP) elevation correlated with the increase in NF-kB activation; therefore, NF-kB may be a cause of the inflammatory paraneoplastic syndrome.” As we Myeloma Club members know, CRP reflects IL-6 activity and is thus an important marker for us. (My CRP, by the way, is within the normal range.) At any rate, I thought it interesting that this study reports a connection between high CRP and NF-kB. Well, well.

Another interesting quote: “Another virus that contributes to human cancer via NF-kB is the Epstein-Barr virus (EBV) implicated in Burkitt’s and Hodgkin’s lymphomas. The EBV nuclear antigen (EBNA)-2 and latent membrane protein (LMP)-1 enhance NF-kB activity thereby preventing apoptosis in EBV-transformed B cells.” While I was in grad school in Toronto, I tested positive for EBV. I was quite ill for about a month, tired all the time, etc., as I recall. Anyway, coincidentally (or…not?), a few years later I was diagnosed with MGUS. Well, I suppose it’s pointless to speculate, but this is not the first time I have read about the EBV-cancer link. Let’s proceed.

I found a fascinating study online (full study: http://tinyurl.com/2ntng6) titled “Good cop, bad cop: the different faces of NF-kB” that appeared in the January 2006 issue of “Cell Death and Differentiation.” It examines the different functions of this transcription factor, including that (drum roll!) of TUMOUR SUPPRESSOR. No kidding. NF-kB can promote both tumour growth and tumour suppression. Bad cop, good cop. How about that?

It is in this study that I read that NF-kB can be triggered by hundreds of “activators.” Hundreds?  Parts of this study are barely intelligible, but I did manage to grasp a few basic concepts. The “classical” or “canonical” NF-kB pathway occurs when this transcription factor translocates, or moves, from the cytoplasm to the nucleus. This is when NF-kB gets activated by inflammatory cytokines such as tumour necrosis factor (TNF)-alpha and IL-1, in response, say, to a bacterial infection. The rest of that particular paragraph is not meant for non-scientific brains, for sure. So, skip, skip, skip! What matters is that at the end of this complicated process of activation, NF-kB ends up in the cell’s nucleus. This can occur in a matter of minutes. Amazing, eh? Then, once it has performed its good cop duties, under normal circumstances, NF-kB is escorted back (by a gene called IKB-alpha) to the cytoplasm, a process I mentioned briefly in my earlier post.

Then we have the “noncanonical” or “alternative” NF-kB pathway, which is activated by other kinases and, for instance, chemotherapy drugs. Some stimuli, such as UV-C (Short-wave ultraviolet radiation), activate NF-kB both by IKK-dependent and IKK-independent pathways.  Ok, ok, my eyes are glazing over, too, and besides, I don’t want to get into too many details. Let’s stay focused on the main points.

Under certain conditions and in response to certain types of stimuli, it would appear that NF-kB can have proapoptotic effects. This “is consistent with the hypothesis that it is the mechanism of induction of NF-kB that determines its physiological function.” It’s all a matter of context, in other words. The important thing is that “If differences in the NF-kB response to a chemotherapeutic drug also occur in different tumors in patients or between patients with apparently the same type of cancer, the ability to more accurately diagnose NF-kB status could profoundly affect treatment choice and outcome.” (Apart from that unfortunate split infinitive, this is quite an interesting statement.)

We already know that NF-kB has pro-inflammatory effects. But the study shows that “NF-kB activity can also be required for the resolution of an inflammatory response. NF-kB activity in the later stages of inflammation has been associated with induction of anti-inflammatory genes and the induction of cell death. Moreover, inhibition of this late-stage NF-kB activity extended the length of the inflammatory response, inhibited the expression of p53 and Bax, and prevented apoptosis.” So sometimes NF-kB can reduce inflammation. I am not sure what late-stage NF-kB activity means, but the inhibition of the tumour-suppressing p53 gene is certainly not a good thing. More research needed.

Now read this shocker: “Because NF-B can perform a tumor suppressor function in some tissues, will its inhibition actually promote cancer in some situations?” Ouch!

The answer is: probably not, since treatment is “relatively short term,” and thus its inhibition of NF-kB would not have enough time to give rise to cancer. So the inhibition of NF-kB, the study states, seems to be the best approach to treating cancer. If the treatment were long-term, though, such as in the treatment of chronic inflammatory diseases, the “continuous suppression of NF-kB activity over a number of years could manifest itself in, for example, squamous cell carcinoma.”

This is a real head-scratcher. A "damned if you do, damned if you don’t" situation. I’d better stop here before my brain melts. But I have not finished with this topic. Not at all.

A quick update before I sign off to go feed the cats: since my so-so test results, I have introduced flaxseed oil capsules into my protocol, also because Sherlock is taking them, too. A slight change. I will update my protocol soon. Have a great weekend, everyone!