Phospholipase Cε as a potential molecular target for anti-inflammatory therapy and cancer prevention

Abstract

Phospholipase Ce (PLCe), encoded by PLCE1, is the phosphoinositide-specific PLC regulated by the ras proto-oncogene product Ras and its relative Rap1. Like other PLC isoforms, PLCe catalyzes hydrolysis of phosphatidylinositol 4,5-bisphosphate to yield second messengers, diacylglycerol and inositol 1,4,5-trisphosphate. To understand the physiological function of PLCe, we have created and analyzed genetically-modified mice in which PLCe is inactivated or overproduced. PLCe knockout (KO) mice are resistant to two-stage skin chemical carcinogenesis initiated by 7,12-dimethylbenz[a]anthracene and promoted by phorbol 12-myristate 13-acetate (PMA) and to intestinal tumorigenesis caused by the loss-of-function mutation of the APC tumor suppressor gene. In PLCe KO mice, inflammation, such as that induced by a single application of PMA, that associated with tumorigenesis, and that in the elicitation phase of allergic contact hypersensitivity, is also attenuated as compared to that in wild-type mice. Conversely, overexpression of PLCe in the epidermis results in the development of skin inflammation that partly shares the features with human psoriasis. In this article, we summarize the data showing the role of PLCe in tumorigenesis and inflammation and discuss the future directions of the study of PLCe for the development of therapies to control inflammation and to prevent cancer progression.