Connecting the Warburg Pathway to Cancer Growth

Armed with new insights about the way cancer cells fuel their growth, Baylor College of Medicine researchers are working with colleagues in New York to explore new possibilities for cancer treatment, particularly breast cancer.

Their work solved a century-old mystery about the Warburg pathway—a process most cancer cells use to generate energy via glucose fermentation.

Bert O’Malley, M.D., considered a founding father in the field of molecular endocrinology, sits for a portrait in his office.

Bert O’Malley, M.D., a founding father in the field of molecular endocrinology and the longtime chair and professor of Baylor’s department of molecular and cellular biology, is leading the team. Members include researchers from Roswell Park Comprehensive Cancer Center in Buffalo, New York.

The team discovered a connection between PFKFB4, an enzyme in the Warburg pathway, and the glucose-driven activation of a protein called SRC-3.

SRC-3 (steroid receptor coactivator-3) was identified as an important regulator of gene expression years ago in O’Malley’s laboratory. Once sparked by PFKFB4, the protein becomes an oncogene—a gene that can cause cancer and its rapid growth and metastasis.

“We knew SRC-3 was the key to cancer growth, and we knew what could affect SRC-3, but we didn’t know sugar could,” said O’Malley, now chancellor of Baylor College of Medicine. “In fact, nobody knew the Warburg pathway did anything to the oncogene or that the enzyme could activate the protein.”

Meet Otto Warburg

The Warburg effect is named for Otto Warburg, M.D., Ph.D., a German physiologist who won a Nobel Prize in 1931 for his work investigating the metabolism of tumors and the respiration of cancer cells. He is the namesake of two observations in biochemistry: a pathway in plant physiology and another pathway in oncology.

Warburg hypothesized that cancer growth stemmed from tumor cells generating energy—called adenosine triphosphate, or ATP—through the anaerobic breakdown of glucose, known as fermentation. This is in contrast to normal cells, which get energy from converted glucose called pyruvate in a process known as glycolysis.

In a biographical sketch of Warburg chronicled by the National Institutes of Health, Warburg said this about his hypothesis during a 1966 lecture:

“Cancer, above all other diseases, has countless secondary causes. But, even for cancer, there is only one prime cause … the replacement of the respiration of oxygen in normal body cells by a fermentation of sugar.”

By activating SRC-3, the Warburg pathway unleashes one of the most potent oncogenes responsible for the spread of breast and other cancers.

“It is the second-most expressed oncogene in all of the human cancers,” O’Malley said. “Normally, it plays a nice little function to keep the cell going, but when it gets over-activated, the cancer cell uses it to drive all of the processes for cell division and replication.”

This happens when the sugar activates the PFKFB4 enzyme, which then phosphorylates the SRC-3 oncogene, making it go from inactive to active and stimulating all the genes to grow the cancer.

Generating cell energy

Though some cells choose the Warburg pathway to make ATP, it is not the only way normal cells produce energy from glucose.

The other way takes place in the mitochondria—the powerhouse of the cell—which yields significantly more energy than theWarburg pathway, explained O’Malley, who also served as Baylor’s Thomas C. Thompson Chair in Cell Biology and associate director of basic research in the Dan L Duncan Comprehensive Cancer Center.

Still, about 80 percent of cancer cells switch to the Warburg pathway, preferring to generate ATP via fermentation, he noted.

“Cancer cells need a lot of energy, so people have wondered why the cancer cells do this,” O’Malley said. “They have hypothesized that this pathway must provide other things the cancer cells want. That is the mystery we shed new light on with our study—that the Warburg is also activating the SRC-3 oncogene that drives the cancer cell to grow.”

The findings appear in a paper in the April 12, 2018 issue of the journal Nature. Subhamoy Dasgupta, Ph.D., the first author on the study, is an assistant professor of oncology at Roswell Park who completed his post-doctoral fellowship in O’Malley’s lab at Baylor.

Removing PFKFB4 or SRC-3 from the tumors suppresses breast tumor growth in the study’s mice model, Dasgupta explained in the abstract.

With that knowledge, the research group is working on therapies to directly target SRC-3, including developing drugs that bind to the protein and inactivate it.

Team members are studying the effects of these drugs on breast cancer in animal models and could be ready to do a Phase 1 clinical trial in humans as early as next year.