Cancer Targets Part I: NF Kappa B

Treatments for cancer can end up killing the patient, or at least killing large parts of the patient which the patient needed. More selective, better targeted treatments are needed, that will kill the cancer cells but leave normal cells alone. Researchers have spent a great deal of time identifiying crucial differences between cancer cells and normal cells, in order to find specific therapeutic targets in the cancer.

In the context of cancer therapy, NF-kappa B (NF-kB) has been found to protect several cancer types from apoptosis, programmed cell suicide. Since much of cancer treatment involves trying to induce apoptosis in the cancer, NF-kB is standing in the way of treatment. It makes sense to try to disable the active NF-kB, so the cancer cell can commit suicide.

This Eurekalert newsrelease looks at three cancer targets. Today, I will discuss the first target in the newsrelease, NF-kappa B. NF-kappa B is a transcription factor that activates genes involved in protecting cells from apoptosis, and several other cellular actions.

In their study, the NCI researchers set out to determine the role of NF-kB in reversing the apoptotic (or programmed cell death) effect of selective estrogen receptor modulators (SERMs) in brain cancer, as well as potential therapies that can be used either alone or in combination to block the protein. High levels of NF-kB are activated and present in transplanted glioma cells and glioma tumor samples, but not in normal brain tissue cells.

SERMs have shown some value in inducing cell death in brain cancers by a previously unknown method. They are designed to deliver the benefits of estrogen without its negative side effects, although gliomas do not generally express the estrogen receptor. However, previous studies have shown that NF-kB protects glioma cells from breaking down, therefore reversing the effect of SERM therapies.

Researchers looked at 203 glioma samples and determined that NF-KB was activated. They also noticed that the level of activation was related to the grade of the tumor, suggesting that NF-KB is related to tumor progression.

....IkB-alpha is one of a series of inhibitory proteins that controls the activation of NF-kB, preventing it from binding to DNA in the nucleus. Bortezomib not only stops the degradation of IkB-alpha, it also suppresses the activation of NF-kB, thus stopping cell growth.

"By interfering with the function of IkB-alpha proteins, bortezomib was shown to induce glioma cell degradation and enhance anti-cancer effects of SERMs," said Ai-Min Hui, M.D., Ph.D., research fellow at the National Cancer Institute and lead investigator on this trial.

Read more here.

NF-kB will be central to many future treatments of cancer, and inflammatory disease--such as rheumatoid arthritis. That is because NF-kB is central to the transcription of mRNAs for proteins involved in inflammation, the cell growth cycle, and protecting cancer from apoptosis.

For more information on this important cell signal transduction pathway, consult these references:

http://people.bu.edu/gilmore/nf-kb/

http://www.jci.org/cgi/content/full/107/2/135

MIT World Video--David Baltimore: "The Many Faces of NF-Kappa B"

It would be impossible to exaggerate the key importance of this transcription factor, for research into cancer, immunology, rheumatology, ageing, and other important areas of biomedicine. More on cancer targets 2 and 3 later.