The cellular protein STAT3 is implicated in the differentiation and proliferation of many cancers, including leukemia, lymphoma, and breast, prostate, and brain tumors. STAT3 is a master gene regulator—responding to intracellular signals gone wrong, it can enter the cell's nucleus, bind to DNA, and unleash a cascade of events that promotes distorted and unchecked cell growth.
“Numerous cancer cell types rely upon STAT3 for survival,” explains Patrick Gunning of the University of Toronto at Mississauga, senior author of a paper published in June (Angew Chem Int Ed 2011;50:6248–53). “Inhibiting hyperactivated STAT3 signaling in a cancer cell may sensitize cells to chemotherapy. Encouragingly, normal cells seem able to withstand inhibition of STAT3, making it an appealing target.”
Unfortunately, “STAT3 is extremely difficult to target,” adds Gunning. “That's why there aren't any STAT3-targeting drugs in the clinic yet.”
Gunning and his colleagues are taking an innovative tack: They developed a dumbbell-shaped protein-membrane anchor that prevents STAT3 from moving into the nucleus. A cholesterol molecule at one end of the compound hooks into the cell membrane, while a molecule at the other end binds to the cancer-promoting protein, blocking its rendezvous with DNA.
A series of in vitro fluorescence-based experiments, including work in human breast-cancer cells, indicated that the technique is effective in pinning STAT3 to cell membranes. The work is the first example of a protein-membrane anchor that can capture and immobilize a cancer-promoting protein, says Gunning. The Toronto team plans to sequester other proteins and study their compound's effectiveness against leukemia and breast cancer in animal models.