Tag Archives: pyroptosis

Do we finally know what MYC is doing in cancer?

Tens of thousands of papers have been written on what MYC might be doing in cancer.  I’ve been reading about Myc for years, and my notes on Myc  contain 60,000+ characters. Cancer cells must love MYC as around 70% of human cancers overexpress the MYC protein, which is a transcription factor turning on the expression of at least 1,500 genes.  Others say 2,000 ( 10% of all protein coding genes).  “Whatever the latest trend in cancer biology — cell cycle, cell growth, apoptosis, metabolism, cancer stem cells, microRNAs, angiogenesis, inflammation — Myc is there regulating most of the key genes”  [ Cell vol. 151 pp. 11 – 13 ’12 ].   An intriguing theory is that Myc is part of the Matthew syndrome — Matthew 25:29
“For everyone who has will be given more, and he will have an abundance.”  Translating this into molecular biological terms, Myc acts to amplify the transcriptional state of any gene which is actively being transcribed.

The old idea that cells just up and died when they got sick, is pretty much gone.  There are various types of cell death, each of which has an intricately programmed mechanism — apoptosis, ferroptosis, pyroptosis, and necroptosis.  The latter is common on cancer, particularly when attacked by the immune system. [ Proc. Natl. Acad. Sci. vol. 117 pp. 19982 – 19993 20 ] says that MYC acts as an antinecroptosis factor by inhibiting the interaction of RIPK1 and RIPK3 which goes on to trigger necroptosis. This may be why cancer cells so love MYC.  What is particularly fascinating (to neurologists at least) is that further along the path to necroptosis another protein (MLKL) forms cytoplasmic amyloid fibers as part of the process.  So here is a physiological use for amyloid (even though the net result is death).

Never stop thinking, never stop looking for an angle

Derek Lowe may soon be a very rich man if he owns some Vertex stock. An incredible pair of papers in the current Nature (vol. 505 pp. 492 – 493, 509 – 514 ’14, Science (vol 343 pp. 38 – 384, 428 – 432 ’14) has come up with a completely new way of possibly treating AIDs. Instead of attacking the virus, attack the cells it infects, and let them live (or at least die differently).

Now for some background. Cells within us are dying all the time. Red cells die within half a year, the cells in the lining of your gut die within a week and are replaced. None of this causes inflammation, and the cells die very quietly and are munched up by white cells. They even send out a signal to the white cells called an ‘eat me’ signal. The process is called apoptosis. It occurs big time during embryonic development, particularly in the nervous system. Neurons failing to make strong enough contacts effectively kill themselves.

Apoptosis is also called programmed cell death — the cell literally kills itself using enzymes called caspases to break down proteins, and other proteins to break down DNA.

We have evolved other ways for cell death to occur. Consider a cell infected by a bacterium or a virus. We don’t want it to go quietly. We want a lot of inflammatory white cells to get near it and mop up any organisms around. This type of cell death is called pyroptosis. It also uses caspases, but a different set.

You just can’t get away from teleological thinking in biology. We are always asking ‘what’s it for?’ Chemistry and physics can never answer questions like this. We’re back at the Cartesian dichotomy.

Which brings us to an unprecedented way to treat AIDS (or even prevent it).

As anyone conscious for the past 30 years knows, the AIDS virus (aka Human Immunodeficiency Virus 1 aka HIV1) destroys the immune system. It does so in many ways, but the major brunt of the disease falls on a type of white cell called a helper T cell. These cells carry a protein called CD4 on their surface, so for years docs have been counting their number as a prognostic sign, and, in earlier days, to tell them when to start treatment.

We know HIV1 infects CD4 positive (CD4+) T cells and kills them. What the papers show, is that this isn’t the way that most CD4+ cells die. Most (the papers estimate 95%) CD4+ cells die of an abortive HIV1 infection — the virus gets into the cell, starts making some of its DNA, and then the pyroptosis response occurs, causing inflammation, attracting more and more immune cells, which then get infected.

This provides a rather satisfying explanation of the chronic inflammation seen in AIDS in lymph nodes.

Vertex has a drug VX-765 which inhibits the caspase responsible for pyroptosis, but not those responsible for apoptosis. The structure is available (http://www.medkoo.com/Anticancer-trials/VX-765.html), and it looks like a protease inhibitor. Even better, VX-765 been used in humans (in phase II trials for something entirely different). It was well tolerated for 6 weeks anyway. Clearly, a lot more needs to be done before it’s brought to the FDA — how safe is it after a year, what are the long term side effects. But imagine that you could give this to someone newly infected with essentially normal CD4+ count to literally prevent the immunodeficiency, even if you weren’t getting rid of the virus.

Possibly a great advance. I love the deviousness of it all. Don’t attack the virus, but prevent cells it infects from dying in a particular way.

Never stop thinking. Hats off to those who thought of it.