A new study, entitled “TIPE3 Is the Transfer Protein of Lipid Second Messengers that Promote Cancer” published on Cancer Cell by first author Dr. Svetlana Fayngerts from Dr. Youhai Chen’s group, Department of Pathology and Laboratory Medicine at the Perelman School of Medicine, University of Pennsylvania, reported that TIPE3, a novel oncogenic protein, is the transfer protein of phosphoinositide second messengers responsible for colon cancer progression.
Lipid second messenger molecules, such as phosphoinositide lipids, within cellular membranes relay, increase, and diversify cell surface receptor signals. The signals induced by these lipid molecules are unusually increased in more than 50% of human cancers, but their regulation during tumor formation is not clear. One of the best described lipid chemical messengers is phosphatidyl-inositol,3,4,5 triphosphate (PIP3), which relays signals from hundreds of membrane receptors, including many oncogenic receptors. PIP3 is the main substrate for an important pathway that regulates the signaling of multiple essential biological processes like cell growth, differentiation, migration, transformation, and death.
In this study, researchers identified TIPE3 as the transfer protein of the second messenger PIP3 that is manipulated by cancer cells to escape cell division. TIPE3 belongs to the tumor necrosis factor (TNF)-alpha-induced protein 8 (TNFAIP8 or TIPE) family, a group of proteins recently linked to an important role in immune homeostasis. TIPE3 is a susceptibility factor for human cancer and inflammation, although its mechanisms of action are not well known.
The researchers performed a high-resolution crystal structure of TIPE3, identifying a large cavity where phosphatidylinositol 4,5-bisphosphate (PIP2), a PIP3 precursor, along with PIP3 are captured and transported, increasing their levels in the inner side of the cell membrane, and promoting the activation of downstream PIP3 effectors molecules.
Thus, PIP3 seems to be a good candidate to be targeted by specific drugs for the treatment of cancer and inflammatory disorders. Notably, not only colon, but many types of human cancers like lung, ovarian, and esophageal have strikingly higher TIPE3 expression. Therefore, the authors blocked the expression and removed the TIPE3 gene from both cells in vitro and mice in vivo, observing a decrease in malignant tumor cell growth and inhibition of 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,” Dr. Chen said in a University of Pennsylvania press release. “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,” added Dr. Chen.
Currently, these researchers are addressing ways to control atypical expression of TIPE3 to treat or prevent cancer.