Molecular pathways: adiponectin and leptin signaling in cancer

Abstract

The increasing percentage of obese individuals in the population and its independent association of increased risk for the development of cancer have heightened the necessity to understand the molecular mechanisms that underlie this connection. The deregulation of adipokines in the setting of obesity and their impact on cancer progression and metastasis is one such area of research. Adipokines are bioactive proteins that mediate metabolism, inflammation, angiogenesis, and proliferation. Altered levels of adipokines or their cognate receptors in cancers can ultimately lead to an imbalance in downstream molecular pathways. Discovery of adipokine receptors in various cancers has highlighted the potential for novel therapeutic targets. Leptin and adiponectin represent two adipokines that elicit generally opposing molecular effects. Epidemiologic studies have highlighted associations between increased serum leptin levels and increased tumor growth, whereas adiponectin exhibits an inverse correlation with cancer development. This review addresses the current level of understanding of molecular pathways activated by adiponectin and leptin to identify the areas of intervention and facilitate advancement in the field.

Figure 1

Leptin and adiponectin activate signaling components that integrate PI3K/Akt, RAS/MAPK, and pAMPK/mTor pathways. Green arrows indicate activation of target protein, while red lines indicate inhibitory effects. Leptin stimulation of the long receptor isoform leads to JAK2 phosphorylation and subsequent phosphorylation of tyrosine residues 985 and 1138, which confer PI3K/Akt and STAT3 pathway activation. Leptin stimulation can be prevented with c-reactive peptide, soluble leptin receptor (Ob-Re) or leptin antagonists. Chronic stimulation leads to an increase in SOCS3 which negatively regulates leptin signaling by inhibiting JAK2 activities. Additionally, leptin receptor stimulation activates SHP2 leading to increased Ras/RAF/ERK signaling. Adiponectin receptor 1 (AdipoR1) and receptor 2 (AdipoR2) are preferentially stimulated by the globular (gAdn) and high molecular weight (HMW Adn) oligomers of adiponectin respectively, although both receptors respond with lower affinity to other adiponectin oligomers. Serum levels of adiponectin can be increased through thiazolidinediones or fenofibrates, while the receptor levels can be increased with rosiglitazone or exercise. Adiponectin receptors associate with adaptor protein APPL1 to activate AMPK and PPAR alpha. Adiponectin can antagonize leptin mediated proliferation through activation of phosphatase PTP1B, leading to inhibition of JAK2, dephosphorylation of STAT3, and dephosphorylation of ERK1/2; as well as phosphatase PP2A to decrease phosphor-Akt. Adiponectin also inhibits leptin action through increased AMPK inhibition on mTORC1 directly as well as indirectly through TSC2. Metformin additionally antagonizes leptin action through activation of AMPK. Adiponectin activation also leads to modulation of NFkB, TP53, eNOS, ACC, and ceramidase activity; yet direct antagonism of leptin through these mediators is unclear. Ultimate outcome for a particular pathway in cancer is highly dependent upon genetic integrity and deficiencies in key regulatory mediators will dictate which pathway will dominate.