Apelin/APJ: Another Player in the Cancer Biology Network

Abstract

The apelinergic system exerts multiple biological activities in human pathologies, including cancer. Overactivation of apelin/APJ, which has been detected in many malignant tumors, and the strong correlation with progression-free and overall survival, suggested the role of an oncogene for the apelin gene. Emerging evidence sheds new light on the effects of apelin on cellular functions and homeostasis in cancer cells and supports a direct role for this pathway on different hallmarks of cancer: "sustaining proliferative signaling", "resisting cell death", "activating invasion and metastasis", "inducing/accessing vasculature", "reprogramming cellular metabolism", "avoiding immune destruction" and "tumor-promoting inflammation", and "enabling replicative immortality". This article reviews the currently available literature on the intracellular processes regulated by apelin/APJ, focusing on those pathways correlated with tumor development and progression. Furthermore, the association between the activity of the apelinergic axis and the resistance of cancer cells to oncologic treatments (chemotherapy, immunotherapy, radiation) suggests apelin/APJ as a possible target to potentiate traditional therapies, as well as to develop diagnostic and prognostic applications. This issue will be also covered in the review.

Keywords: APJ; apelin; cancer; chemoresistance; hallmarks of cancer.

Figure 1

Intracellular pathways and cellular functions modulated by the APJ system. By interacting with G proteins, the binding of the endogenous ligand (apelin or Elabela) to APJ is able to promote the following: the inhibition of cAMP generation and protein kinase A (PKA) and activation of phospho-inositide 3-kinase (PI3K)/AKT through Gi/o; the activation of protein kinase C (PKC)-dependent extracellular signal-regulated kinase 1/2 (ERK1/2) through Gi/o or Gq/11; the initiation of the intracellular release of Ca²⁺ by Gq/11 and inositol 1,4,5-triphosphate (IP3) synthesis; the autophosphorylation of APJ through G protein-coupled receptor kinase (GRK) and initiation of the β-arrestin-mediated cascade; the activation of G13 and inactivation of histone deacetylases (HDAC) type 4 and 5, determining the activation of myocyte enhancer factor-2 (MEF2) and expression of MEF2 target gene Kruppel-like factor 2 (KLF2). Both AKT activation and increase of intracellular Ca²⁺ and β-arrestin induce nitric oxide synthase (NOS). The up arrows indicate upregulation. The down arrows indicate downregulation. ROS: reactive oxygen species.

Figure 2

Modulation and biological effects of the apelin/APJ system in cancer. Hypoxia, generated by the hypermorphosis of cancer cells, upregulates apelin expression by inducing oxidative stress and dependent hypoxia inducible factor (HIF). The overactivation of the apelinergic system in tumor tissue directly contributes to cancer development and progression through the sustainment of several hallmarks of cancer: sustaining proliferative signaling, resisting cell death, activating invasion and metastasis, inducing/accessing vasculature, reprogramming cellular metabolism, avoiding immune destruction and tumor-promoting inflammation, and enabling replicative immortality. The apelin/APJ effect on each hallmark is driven in different malignancies by the modulation of several intracellular pathways. ECM: extracellular matrix.