Tumour co-expression of apelin and its receptor is the basis of an autocrine loop involved in the growth of colon adenocarcinomas

Using a cancer profiling array, our laboratory has shown that apelin gene is up-regulated in half of colon adenocarcinomas. We have therefore postulated that apelin signalling might play a prominent role in the growth of colon tumours. We first confirmed by immunohistochemistry that apelin peptide is overexpressed in human colon adenomas and adenocarcinomas. We also observed a significant overexpression of apelin receptor (APJ) in adjacent sections. We then demonstrated that several colorectal cancer cell lines also expressed apelin and its receptor, the highest gene and peptide expression being detected in LoVo cells. In this cell line, the expression and functionality of apelin receptor were revealed by apelin-induced adenylyl cyclase inhibition and Akt phosphorylation. In addition, apelin clearly protected LoVo cells from apoptosis by inactivating a caspase-dependent pathway and decreasing the degradation of poly ADP ribose polymerase protein (PARP). Finally, treatment of these tumour cells by the (F13A)apelin13 receptor antagonist significantly reduced their proliferation rate. Altogether, these data suggest the existence of an autocrine loop by which constitutive activation of apelin signalling should participate in the growth of colon adenocarcinomas. Accordingly, apelin signalling is a promising pharmacological target for the treatment of human colon adenomas and adenocarcinomas.