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!
Delighted you caught the split infinitive! Good girl!
From Nature 451, 388-389 (2008): That microbes can benefit their hosts is by no means new. For example, bacteria living in the human gut are known to influence immune function, and help our body absorb nutrients. But only recently have scientists suggested that infectious viruses could provide their hosts with benefits as well. Viruses influence the host immune system in significant — and occasionally beneficial — ways, a concept that isn’t surprising when one considers that they have been interacting with immune systems for millions of years.
Recently, Herbert ‘Skip’ Virgin, an immunologist at Washington University School of Medicine in St Louis, Missouri, infected mice with dormant viruses genetically similar to human Epstein–Barr virus and human cytomegalovirus. These viruses, he found, protected the mice from the bacterial pathogens Listeria monocytogenes and Yersinia pestis . Virgin and his colleagues suggest that the viruses upregulate the production of immune factors that prevent further infection rather than interacting directly with the microbes2.
So EBV may help in certain situations and hurt in others. In short this subject to far to complicated and in its research infancy. I personally think EBV is an insidious little beast.