Understanding cancer energetics

June 4, 2011

(Medical Xpress) -- It's long been known that cancer cells eat a lot of sugar to stay alive. In fact, where normal, noncancerous cells generate energy from using some sugar and a lot of oxygen, cancerous cells use virtually no oxygen and a lot of sugar. Many genes have been implicated in this process and now, reporting in the May 27 issue of Cell, researchers at the Johns Hopkins University School of Medicine have discovered that this so-called Warburg effect is controlled.

"It turns out to be a feed-forward mechanism, where protein A turns on B, which in turn goes back and helps A do more," says Gregg Semenza, M.D., Ph.D., the C. Michael Armstrong Professor of Medicine, director of the vascular program in Hopkins' Institute for Cell Engineering and a member of the McKusick-Nathans Institute of Genetic Medicine. "PKM2 normally functions as an enzyme involved in the metabolism of glucose, but in this case we have demonstrated a novel role in the control of gene expression in cancer ."

Nearly 20 years ago, Semenza's research team discovered that HIF-1 can turn on a number of that that help cells survive when oxygen levels fall too low. In addition to genes that contribute to building new blood vessels, HIF-1 also turns on genes involved in the metabolic process that turns glucose into energy. One of those genes, pyruvate kinase M2 or PKM2, catalyzes the first step of this and is present only in cancer cells.

To figure out whether and if HIF-1 and PKM2 interact, the team first engineered cells to have or lack HIF-1. They kept them in high or low oxygen for 24 hours and found that cells starved of oxygen, but containing HIF-1, had more PKM2 than cells without HIF-1, suggesting that HIF-1 controls the production of PKM2.

The team then asked if HIF-1 and PKM2 physically interact with each other by isolating one of the two proteins from cells; they found that pulling one out also resulted in the other coming along for the ride, showing that the two proteins do in fact bind to each other.

Knowing that the primary function of HIF-1 is to bind DNA and turn on specific genes, Semenza's team next asked whether PKM2 somehow helped HIF-1 do that. They examined genes known to be activated by HIF-1 in low oxygen after the removal of PKM2 and found that without PKM2, less HIF-1 was bound to DNA.

Now armed with evidence that PKM2 helps HIF-1 turn on genes, the team looked at the activity of genes directly involved in the metabolic pathway that burns so much sugar in and compared genes known to be activated by HIF-1 with those not affected by HIF-1. Removing PKM2 from cells had no effect on genes not controlled by HIF-1 but reduced the activity of HIF-1-controlled genes.

"These results were really astounding," says Semenza. "In addition to solving the long-standing mystery of the Warburg effect, we also discovered that PKM2 may play a far broader role in promoting progression than has been appreciated before."

Related Stories

Recommended for you

Study may explain failure of retinoic acid trials against breast cancer

July 25, 2017
Estrogen-positive breast cancers are often treated with anti-estrogen therapies. But about half of these cancers contain a subpopulation of cells marked by the protein cytokeratin 5 (CK5), which resists treatment—and breast ...

Physical activity could combat fatigue, cognitive decline in cancer survivors

July 25, 2017
A new study indicates that cancer patients and survivors have a ready weapon against fatigue and "chemo brain": a brisk walk.

Breaking the genetic resistance of lung cancer and melanoma

July 25, 2017
Researchers from Monash University and the Memorial Sloan Kettering Cancer Center (MSKCC, New York) have discovered why some cancers – particularly lung cancer and melanoma – are able to quickly develop deadly resistance ...

New therapeutic approach for difficult-to-treat subtype of ovarian cancer identified

July 24, 2017
A potential new therapeutic strategy for a difficult-to-treat form of ovarian cancer has been discovered by Wistar scientists. The findings were published online in Nature Cell Biology.

Immune cells the missing ingredient in new bladder cancer treatment

July 24, 2017
New research offers a possible explanation for why a new type of cancer treatment hasn't been working as expected against bladder cancer.

Anti-cancer chemotherapeutic agent inhibits glioblastoma growth and radiation resistance

July 24, 2017
Glioblastoma is a primary brain tumor with dismal survival rates, even after treatment with surgery, chemotherapy and radiation. A small subpopulation of tumor cells—glioma stem cells—is responsible for glioblastoma's ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.