The role of adiponectin in cancer: a review of current evidence

Abstract

Excess body weight is associated not only with an increased risk of type 2 diabetes and cardiovascular disease (CVD) but also with various types of malignancies. Adiponectin, the most abundant protein secreted by adipose tissue, exhibits insulin-sensitizing, antiinflammatory, antiatherogenic, proapoptotic, and antiproliferative properties. Circulating adiponectin levels, which are determined predominantly by genetic factors, diet, physical activity, and abdominal adiposity, are decreased in patients with diabetes, CVD, and several obesity-associated cancers. Also, adiponectin levels are inversely associated with the risk of developing diabetes, CVD, and several malignancies later in life. Many cancer cell lines express adiponectin receptors, and adiponectin in vitro limits cell proliferation and induces apoptosis. Recent in vitro studies demonstrate the antiangiogenic and tumor growth-limiting properties of adiponectin. Studies in both animals and humans have investigated adiponectin and adiponectin receptor regulation and expression in several cancers. Current evidence supports a role of adiponectin as a novel risk factor and potential diagnostic and prognostic biomarker in cancer. In addition, either adiponectin per se or medications that increase adiponectin levels or up-regulate signaling pathways downstream of adiponectin may prove to be useful anticancer agents. This review presents the role of adiponectin in carcinogenesis and cancer progression and examines the pathophysiological mechanisms that underlie the association between adiponectin and malignancy in the context of a dysfunctional adipose tissue in obesity. Understanding of these mechanisms may be important for the development of preventive and therapeutic strategies against obesity-associated malignancies.

Figure 1.

Signaling pathways connecting adiponectin to carcinogenesis. Adiponectin may act on cancer tissues either by sequestrating growth factors at the prereceptor level or by binding to AdipoR1, AdipoR2, and T-cadherin. T-Cadherin has not been associated with downstream effector molecules and may serve as a coreceptor for adiponectin. Binding to AdipoR1 and AdipoR2, initiates a cascade of signaling molecules comprising, among others, activation of AMPK by the cofactors LKB1, APPL-1, and/or CaMKK; induction of Bax and cAMP/PKA; as well as inhibition of ERK1/2, PI3K/Akt, Wnt/β-catenin, nicotinamide adenine dinucleotide phosphate-oxidase/ROS/MAPK, NF-κB, Bcl-2, and JAK2/STAT3 signaling. Activated AMPK subsequently stimulates JNK, PP2A, and the cell cycle regulators p53/p21/p27, while negatively influencing fatty acid synthase (FAS)/ACC and the mTOR/S6K axis. Collectively, these effects result in reduced fatty acid and protein synthesis; decreased cellular growth, proliferation, and DNA-mutagenesis; and increased cell cycle arrest and apoptosis, thus negatively influencing carcinogenesis. Cross talk between the mentioned pathways adds further complexity to the adiponectin-induced signaling network. Finally, recent advances show that adiponectin can enhance ceramidase activity independently from AMPK via AdipoR1/R2, contributing to increased amounts of prosurvival S1P. The black and red lines indicate stimulatory and inhibitory effects, respectively. Trx, Thioredoxin.