Researchers from Baylor College of Medicine and Roswell Park Comprehensive Cancer Center have found how cancer cells use the Warburg pathway enzyme PRKFB4 to activate SRC-3, a driver of breast cancer. The work was published yesterday in Nature.
According to authors, about 80% of cancer cells generate energy via fermentation. This process is known as the Warburg effect, which many signaling pathways contribute to. "This has been a mystery for quite some time. Why would cancer cells, which need large amounts of energy to sustain their growth, prefer to use a pathway that produces less ATP than another available pathway?" senior author Bert O'Malley said. "What would be the advantage for cancer cells to use the Warburg pathway? Our study sheds new light on this mystery."
The O'Malley lab has identified SRC-3 as a protein that is often overproduced and if modified, SRC-3 can become hyperactive, a hallmark of many tumors.
"We conducted an unbiased search to identify enzymes that add phosphate groups that are able to enhance the activity of SRC-3," said first author Subhamoy Dasgupta.
"We were surprised to identify an enzyme named PFKFB4 as one of the most dominant regulators of protein SRC-3. This was unexpected because PFKFB4 was well known for its ability to only add phosphate groups to sugars in the Warburg pathway. Nobody had described before that this enzyme could also add phosphate groups to proteins," Dasgupta said.
"When PFKFB4 adds a phosphate group to SRC-3, it transforms it into a potent driver of breast cancer and other cancers as well," O'Malley said.
"I am most excited about our findings regarding breast tumor progression in mouse models," said Dasgupta. "Our data shows that by removing PFKFB4 or SRC-3 from the tumors, we are able to almost completely eliminate recurrence and metastasis of breast cancer. In addition, modification of SRC-3, so it cannot receive a phosphate group, also results in tumor control."
"One of the most interesting things to me is that we have solved some of this nearly 100-year-old mystery," O'Malley said. "Also, our findings give us more potential intervention points for future therapies. This is important because breast cancer recurrence and metastasis are clinically challenging problems."