Dr. Lorne Brandes: Prion-like behaviour of a vital cell protein linked to cancer

In my last two blogs, I discussed the role that prion-like proteins play in normal brain function, where they are key players in forming long-term memory, and in neurodegenerative disorders, such as Alzheimer’s dementia and Parkinson’s disease, where they go awry and progressively erase memory… a double-edged sword by anyone’s definition.

Yet, if that stunning revelation isn’t enough, a paper just published in the Journal of Biological Chemistry has, for the first time, definitively linked a prion-like protein to cancer!

To help you understand this ground-breaking discovery, let me once again briefly review some important facts about prions.

• Prions are important proteins made by our genes. They normally exist as single water-soluble molecules that line up along nerve cell membranes to transport iron and copper, vital to nerve function, into the cells.
• Under certain conditions, several prions clump together to form insoluble “oligomers” (from the Greek, “oligo”, meaning “a few”). When this occurs, the normal prion shape changes from a corkscrew (called an “alpha-helix”) into a misfolded pleated form called a “beta-sheet”.
• Unlike alpha-helix prion proteins, beta-sheet oligomers replicate, using themselves as templates to form other oligomers.
• Prion oligomers somehow induce many other single prions to clump into oligomers. When this occurs, the oligomer form dominates and normal (single) prion function is lost (an important point to remember when we get to the cancer story).

While we now know that, like single prions, oligomers are also part of nature’s plan (the retention of long-term memory is an example), for poorly-understood reasons they sometimes violate nature by morphing into infectious rogue proteins (the name “prion” was originally derived from protein infection) that spread throughout the brain, killing nerve cells.

The first neurodegenerative disease linked to infectious prion oligomers was scrapie in sheep, followed by bovine spongiform encephalopathy (BSE; mad cow disease) in cattle, and kuru and Creutzfeldt-Jakob disease in humans.

With recent discoveries that nerve-killing proteins linked to Alzheimer’s dementia (beta-amyloid and tau), Parkinson’s disease (alpha-synuclein) and amyotrophic lateral sclerosis (SOD1) are all dominant beta-sheet oligomers, scientists now believe that many, if not all, neurodegenerative diseases in humans may turn out to be prion disorders, a truly important conceptual breakthrough.

With that as background, let us move out of the brain into cancer cells, where a mutated protein has been found to have prion-like properties.

What makes this such an important story is that we are not talking about just any protein, but one known as p53. Called the “guardian of the genome”, p53 is a major player in protecting our DNA from environmental damage that, if left unchecked, can lead to cancer.

How does p53 do this? By temporarily stopping damaged cells from dividing so that the DNA can be repaired; when the genetic damage is too severe to fix, p53 initiates a chain reaction that kills the cell (a process called “apoptosis”) before it becomes dangerous.

Although it protects our genes, p53 is itself a gene product. A series of landmark studies in the 1980’s and 90’s led to the discovery that mutations in the gene that encodes p53 (called the “p53 tumour suppressor gene”) are responsible for more than half of all human cancers. Inheriting a single mutated p53 gene from either parent results in the development of multiple cancers, starting from childhood (Li-Fraumeni syndrome).

Up until now, we have known that these cancers occur because, unlike normal (“wild-type”) p53, mutated p53 is inactive. The long-unanswered question has been how a mutation blocks its ability to function as the cell’s “guardian”.

But now, a team of scientists, led by Dr. Jerson Lima Silva at Rio de Janeiro’s Federal University, has made several provocative findings:

• A common mutant p53 protein, called R248Q, has a high propensity to clump and misfold into insoluble beta-sheet oligomers.
• Under the microscope, the mutant p53 oligomers form beta-amyloid fibres, identical to the substance that accumulates in the brains of patients with Alzheimer’s dementia.
• In cultured breast cancer cells, the mutant p53 oligomers act like dominant prions, causing wild-type p53 molecules to form oligomers as well.
• When that happens, they lose their normal function (in this case, protecting against cancer).

The researchers concluded that, “….[clumping] of [mutant p53] into…oligomers….sequest[ers] the [wild-type] p53 protein into an inactive conformation that is typical of a prionoid. This…. provides an explanation for the negative dominan[t] effect [i.e., loss of protective function] and may serve as a potential target for cancer therapy.

While confirmation from other laboratories will be required, it is my opinion that the Brazilian study is on solid ground; if correct, the findings are certain to lead to the exploration of new avenues of prevention and/or treatment of cancers caused by  p53 mutations.

Here is some additional food for thought:

• Based on the normal function of prionsto transport metals into cells, and the observation that iron  promotes oligomer formation, it has been suggested that mishandling of metals  inside cells could result in the clumping of alpha-helix prions into beta-sheet oligomers. If correct, any disease associated with an abnormal buildup of oligomers (including cancer) might respond to chelating drugs that remove excess metals.
• Two chelators, deferiprone and PBT2, are already in clinical trials in Parkinson’s, Alzheimer’sand Huntington’s disease. If they prove effective to unfold memory-robbing oligomers in the brain, they could also be active against cancer-causing p53 oligomers.
• As an alternative to chelation, intravenous gamma globulin, an immune treatment that directly targets beta-amyloid itself, halted the progression of early Alzheimer’s dementia in a few patients. If this preliminary finding is verified in a soon to be completed large phase 3 trial, gamma globulin might theoretically prevent or halt cancers arising from p53 amyloid oligomers.

Speculation aside, what most intrigues me is that prion-like protein behavior is rapidly being identified across a wide biological spectrum. Suddenly, a light has been turned on in a previously dark tunnel!