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My Wife Steered me to a New York Times Magazine Article that stirred thoughts of Glycolysis

30 May

Figure2a.pngThe late 19th / early 20th century was an interesting time to be alive. My wife and I have recently been reading about the lives of several people living at that time including, Elanor Roosevelt, Dietrich Bonhoeffer, and most recently for me, Nils Bohr. Reading about it naturally leads to talking about it and marveling at the way that this was a time of awakening across the world. Not quite the same as the Renaissance, but more with respect to the nations of the world becoming intertwined and the actions on one side of the globe had real repercussions on the other side. Others living at that time included Mark Twain(1835-1910),  Herman Melville(1819-1891), James Joyce(1882-1941), Franz Kafka(1883 – 1924), Pyotr Tchaikovsky(1840-1893), Johannes Brahms(1833-1897), Vincent Van Gogh(1853-1890), and Auguste Rodin(1840-1917).There are many brilliant minds at all points in history, we’ve recently had scientists such as Richard Dawkins and Craig Venter; Computer makers Steve Jobs and Bill Gates; Musicians Paul McCartney, Yo-Yo Ma and Joshua Bell; and filmmaker John Lasseter, to name a few (not to forget the Kardashians and Paris Hilton).

It was a time of great artists and great scientists. Mark Twain(1835-1910),  Herman Melville(1819-1891), James Joyce(1882-1941), Franz Kafka(1883-1924), Pyotr Tchaikovsky(1840-1893), Johannes Brahms(1833-1897), Vincent Van Gogh(1853-1890), and Auguste Rodin(1840-1917) could run into one another. Mark Twain could have taken Vincent Van Gogh for beer and an earful of clever conversation that acknowledged a crazy world, but didn’t fall into despair because of it.There are many brilliant minds at all points in history, we’ve recently had scientists such as Richard Dawkins and Craig Venter; Computer makers Steve Jobs and Bill Gates; Musicians Paul McCartney, Yo-Yo Ma and Joshua Bell; and filmmaker John Lasseter, to name a few -and lest we forget, we have the Kardashians and Paris Hilton to show us that, while the unexamined life may not be worth living, one populated with innumerable selfies is just HOT!

As there have been brilliant minds at all points in history, we too live in exciting times.  We live in times with scientists such as Richard Dawkins and Craig Venter who make it their duty not to just pursue science, but to share it with the rest of us; Computer makers Steve Jobs and Bill Gates revolutionized the amount of work on person or a small team can do; Musicians Paul McCartney, Yo-Yo Ma and Joshua Bell touch us and unite us with their music; and filmmaker John Lasseter brings life to the lifeless and makes cartoons parents can enjoy just as much as their children do. A.J. Abrams brought Star Wars back from the brink and reminded us why we fell in love with the franchise back before it was a franchise. to name a few (not to forget the Kardashians and Paris Hilton).

But, back to the article.

The  article she told me about that brought up the turn of the last century was part of an ongoing series about Cancer from the New York Times Magazine discussing the Warburg Effect, named for Otto Heinrich Warburg (1883 – 1970). Otto_Heinrich_Warburg_(cropped).jpg I knew of the effect, wherein tumor cells engage in aerobic glycolysis, primarily from the perspective of Craig Thompson’s work unravelling the link between Type II Diabetes and Cancer. That connection is based on Tumor cells’ overexpressing the glucose transporter, GLUT-4. The working model states that: given a sufficient supply of sugar and the ability to mop it up quickly via GLUT-4, the limiting factor in cell growth is not energy, but carbon.

It takes a lot of food to support rapidly growing cells (just look at teenagers). Much of that sugar goes to energy (not as readily apparent in teenagers), but a lot also goes to making the building blocks required for cellular proliferation. But to use the carbon in sugar for building rather than energy means that the sugar cannot be completely broken down to CO2 to be exhaled. Instead, cells break the sugar in half by glycolysis to make pyruvate for a net benefit of only 2ATP per glucose (as opposed to 36 possible). Then the intermediary molecules can be diverted to alternative synthesis pathways for those building blocks.

The basic reactions of Glycolysis are these:

glycolysis.png

However, the last enzyme in the pathway, Pyruvate Kinase can take two forms. The first is a tetrameric enzyme (M2-PK), which efficiently processes PEP into Pyruvate, which can either go on to be aerobically metabolized to generate more ATP or diverted to fermentation reactions.

An alternate, dimeric form, emerges when Pyruvate Kinase interacts with oncoproteins. This form (Tumor M2-PK) reduces the production of pyruvate to a trickle allowing for the buildup of metabolic intermediary molecules which may be diverted to alternate synthesis pathways for building materials.

An illustration comparing the pathway with either dimeric or tetrameric forms is shown here:

glycolysis2.png

[The figure above came from Sybille Mazurek and has been modified for emphasis. Thank you Sybille!]

All this is a much more mechanistic description than Warburg was able to offer in 1924. At that time, it was recognized that tumor cells were switching to glycolysis even with sufficient O2 available, but the best explanation was that perhaps the mitochondria, where the aerobic reactions of cell respiration occur, were broken. He also thought that this disruption was actually the cause of cancer rather than a consequence of other factors leading to cancer and the switch to aerobic glycolysis amongst the sequelae of more fundamental problems.

So, despite the details of his hypotheses proving to be incorrect, what he did get right was the recognition of an important shift in metabolism that occurs in tumor cells.

A lot of research has gone into understanding cancer and into understanding diabetes. An unexpected connection between type II diabetes and cancer led to an unexpected synergy between their research efforts. The connection arises as a result of individuals with  type II diabetes overexpressing insulin as a compensatory measure.

Recall the definition of diabetes and the difference between the type I and type II varieties…

Diabetes is an inability to properly regulate the amount of sugar in the blood. When you eat, insulin levels increase to tell cells to take up the elevated blood sugar that comes soon after.

Type I diabetes is a result of the body destroying the pancreatic islet cells that produce insulin early in life so that the insulin signal never happens and unhealthy amounts of sugar accumulate in the blood.

Type II diabetes (formerly called ‘adult onset’ diabetes before children started getting it) is a result of cells becoming unresponsive to insulin. The association with obesity roughly means that cell so often see insulin that they become accustomed to it and don’t respond appropriately. This is very much like an addiction response. To compensate, the pancreas makes more and more insulin until, eventually, cells are so unresponsive that they just don’t do their job any more and unhealthy amounts of sugar accumulate in the blood.

Two pathways; same outcome.

What this has to do with cancer is that cancer cells are, by their nature, unbounded by many of the rules of other cells. The ones that outlive the others come to dominate the population and before you know it, they’re so numerous and

nrc487381.fig2.jpg

What this has to do with cancer is that cancer cells are, by their nature, unbounded by many of the rules of other cells. The ones that outlive the others come to dominate the population and before you know it, they’re so numerous and resistant to death that they become a health hazard. (If you’re thinking this sounds like evolution on a cellular scale, you’re thinking the right thing.)

One thing that gives one cell an advantage over other ‘lawabiding’ cells in the body is being greedy when food comes around. this is another central problem with cancer. In healthy organisms, cells ‘recognize’ their place and are willing to sacrifice themselves for the good of the body. Cancer cells have reneged on that agreement and look out only for #1.

On a cellular level, this means that they put up receptors for energy-rich molecules like sugar and take it whenever available. One example receptor cancer cells often use for this is GLUT-4. The very same receptor that we saw providing sugar for energy and carbon for building above. It turns out that Insulin binding to insulin receptors triggers the mobility of GLUT-4 receptors from intracellular vesicles to the cell surface. The environment that makes this all possible for tumor cells to do so well is one in which there is excess insulin – like in the circulation of someone who has type II diabetes and has been producing more and more insulin to try to coax cells to take glucose out of the blood.

The take home message:

  • Type II diabetics have very high levels of circulating insulin.
  • Cancer cells can use insulin signals to upregulate glucose-capturing receptors.
  • Cancer cells begin to favor dimeric form of pyruvate kinase.
  • Cancer cells can also perform aerobic glycolysis, the Warburg effect, to get both energy and biological building blocks from this sugar.
  • The cells that do it best have the most (cellular) progeny.

Therefore:   Obesity –> Type II Diabetes –> Cancer

 

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Posted by on May 30, 2016 in Uncategorized

 

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