Surprising study reveals how cancer-causing protein activates

Researchers at Brown Medical School and Rhode Island Hospital have shed new light on the activation of a protein key to the development of cancers, particularly breast and prostate cancer, the most commonly diagnosed cancers in the United States.

The team of cell biologists has discovered a new chemical modification that activates STAT3. This so-called signaling protein is important for embryonic growth and development, helping cells grow, duplicate and migrate. In adulthood, STAT3 presumably falls dormant, but its unexpected and continuous activation causes breast and prostate cells to develop and move through the body.

Eugene Chin, M.D., a Rhode Island Hospital researcher and assistant professor (research) of surgery at Brown Medical School, said experts suspect that environmental factors, such as a diet rich in animal fat and hormones, may activate STAT3.

How the protein is turned on inside cells has been the subject of fiercely competitive research during the last decade. One known trigger is phosphorylation, which modifies some of the tyro-sine and serine amino acids that make up the STAT3 protein. Chin and his team found a second trigger: acetylation, another chemical process that modifies amino acids, such as lysine. Chin said this finding might explain why drugs that only block STAT3 phosphorylation cannot completely stop cancer cells from growing and invading other parts of the body.

“Both tyrosine phosphorylation and lysine acetylation modifications are important events for STAT3 to stimulate cancer cell growth and metastasis,” Chin said. “That’s why the finding is so exciting. Now that we know more about STAT3 activation, we can create better drugs.”

Their findings are published in the current issue of Science.

Paul Yuan, a post-doctoral fellow in Chin’s Rhode Island Hospital lab and the lead author of the paper, painstakingly mutated 47 lysine amino acids and tested each one in cultured cells to see if it activated STAT3. Using this method, Yuan was able to isolate the culprit: Lys685, one of as many as 780 amino acids that are strung together to make the protein.

Yuan corroborated the finding by testing both a normal and mutated version of STAT3 in a mass spectrometer. The machine smashes the protein into amino acids then sequences these building blocks. The work took nearly two years to complete.

Chin said the research provides an important target for drugs in treating breast and prostate cancers that are common in the United States. According to the American Cancer Society, an estimated 217,440 Americans were diagnosed with breast cancer and 230,110 were diagnosed with prostate cancer in 2004. “Finding a drug to block both tyrosine phosphorylation and lysine acetylation of STAT3 protein should be a more effective cancer treatment,” Chin said.

The research team also included Ying-jie Guan, a post-doctoral fellow in the lab, and Devasis Chatterjee, an assistant professor (research) of Medicine at Brown Medical School.