New cancer drug target involving lipid chemical messengers

PHILADELPHIA — More than half of human cancers have abnormally upregulated chemical signals related to lipid metabolism, yet how these signals are controlled during tumor formation is not fully understood.

Youhai Chen, PhD, MD, and Svetlana Fayngerts, PhD, both researchers in the department of Pathology and Laboratory Medicine at the Perelman School of Medicine, University of Pennsylvania, and colleagues report that TIPE3, a newly described oncogenic protein, promotes cancer by targeting these pathways.

Lipid second messengers play cardinal roles in relaying and amplifying signals from outside the cell to its interior and outer membrane. One of the best known lipid second messengers is PIP3, which relays signals from hundreds of membrane receptors, including many oncogenic receptors, on the cell surface to PIP3-binding proteins in the cell's interior, which control cell growth, differentiation, migration, transformation, and death.

Therefore, drugs targeting PIP3 – when its function goes awry -- may be effective for treating a variety of diseases, including cancer and inflammatory disorders. TIPE3 belongs to a newly described family of proteins and is a risk factor for human cancer and inflammation, although its mechanisms of action are largely unknown.

Chen and colleagues discovered that TIPE3 is the transfer protein of the second messenger PIP3 and it is hijacked by cancer cells to cause runaway cell division.

The high-resolution crystal structure of TIPE3 shows a large cavity that captures and transfers PIP3 and its chemical precursor PIP2 to increase their presence on the inner membrane of the cell. This promotes activation of downstream PIP3 effectors that cause cancer.

Importantly, human lung, colon, ovarian, and esophageal cancers have markedly upregulated TIPE3 expression. Knocking down TIPE3 in culture diminishes malignant tumor cell growth and knocking out TIPE3 in mice blocks tumor formation.

"These findings explain why normal cells can control their lipid signals but cancer cells can't, a phenomenon widely recognized, but poorly understood," says Chen. TIPE3 has to be expressed at just the right amount to make sure that the proper signal is transferred, which governs the proper amount of cell division. "Therefore, TIPE3 may represent a new therapeutic target for treating malignant diseases."

The team is now working on strategies to control abnormal TIPE3 expression to treat or prevent cancer.

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Other contributing authors are Jianping Wu, Camilla L. Oxley, Xianglan Liu, Anastassios Vourekas, Terry Cathopoulis, Zhaojun Wang, Jian Cui, Suxia Liu, Honghong Sun, Mark A. Lemmon, Lining Zhang, Yigong Shi.

This work was funded by the National Institute of Allergy and Infectious Diseases and the National Institute of General Medical Sciences (AI-077533, AI-050059, GM-085112).

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