Novel Mechanism May Lead to New Targeted Pharmacological Cancer Treatment

Newswise — (March 28, 2011) PHILADELPHIA -- Inactivation of the retinoblastoma tumor suppressor protein (pRb) by phosphorylation triggers uncontrolled cell proliferation. Accordingly, activation of cyclin-dependent kinase (CDK)/cyclin complexes or downregulation of CDK inhibitors appears as a common event in human cancer.

Now, a new study from the Sbarro Health Research Organization shows that Pin1 (protein interacting with NIMA (never in mitosis) A-), a peptidylprolyl isomerase involved in the control of protein phosphorylation, is an essential mediator for inactivation of the pRB. The findings, published in Cell Death and Differentiation, have important implications for cancer treatment.

“Our findings suggest that the synergism among CDK and Pin1 inhibitors holds great promise for targeted pharmacological treatment of cancer patients with the possibility of reaching high effectiveness at tolerated doses,” said Flavio Rizzolio, lead author of the study. “pRb is one of the most important tumor suppressor genes,” says Antonio Giordano, founder and director of the Sbarro Institute for Cancer Research and Molecular Medicine.

“Understanding the role of Pin1 helps to further clarify the molecular network. “

The researchers identify a new mechanism for pRb inactivation, independent from CDKs and phosphatases. By altering pRb accessibility, Pin1 modifies the activity of CDKs. In such a context, Pin1 thus represents a new therapeutic target that, alone or in combination with CDK inhibitors, may provide a means to limit cancer cell growth via negative modulation of pRb phosphorylation.

“Our study presents, for the first time, a new, detailed mechanism of pRb phosphorylation and suggests a novel approach of treating cancer patients by utilizing Pin1 inhibitors in combination with or without CDK inhibitors,” says Rizzolio. ##The Sbarro Health Research Organization Center for Biotechnology Research funds the Sbarro Institute for Cancer Research and Molecular Medicine, a leading nonprofit research center for cancer, diabetes, and cardiovascular disease. The Director of the Center is Antonio Giordano, M.D., Ph.D., an internationally known pathologist and geneticist.