Introduction

CRC is the third most common cancer and the second leading cause of cancer death [1]. Its initiation is relevant to multi-faceted interactions between host and environment. Some of the important signaling pathways are dysregulated in CRC, including epidermal growth factor receptor (EGFR)-mediated signaling pathways, Wnt signaling, as well as P53, Notch, and eicosanoid signaling pathways [2]. There is strong evidence that proposes mTOR as a key signaling pathway in several cancers, including CRC. The mTOR pathway elevated activity results in translational dysregulation and also acceleration in G1-S phase in colon cancer cell lines [3, 4]. Another significant factor in CRC is the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), an important transcription factor. Constitutive activation of NF-κB has been observed in various malignancies, including CRC, and was included in angiogenesis and tumor growth development. Adiponectin has both stimulatory and inhibitory effects on NF-κB pathway. Adiponectin can downregulate the inhibitor of NF-κB (IκB) phosphorylation resulting in the NF-κB pathway inhibition. Furthermore, adiponectin has been shown to activate NF-κB in C2C12 myocytes. Thus, further studies are required to determine the function of adiponectin in CRC [5, 6]. Impaired regulation of these signaling pathways results in apoptosis elusion, uncontrolled cell progression, induction of genetic instability, and improved metastasis and invasiveness.

Adiponectin, a protein of 244 amino acids and one of the most abundant adipokines, circulates in human plasma in forms of full-length adiponectin (f-adiponectin) or globular adiponectin (g-adiponectin) [7]. Adiponectin receptor has two isoforms: the adiponectin receptor 1 (AdipoR1) and adiponectin receptor 2 (AdipoR2). Adiponectin after binding to its receptors can activate several intracellular pathways, including AMPK/mTOR, mitogen-activated protein kinases (MAPK), and phosphoinositide 3-kinase (PI3K)/AKT [7–10].

Obesity often leads to impaired regulation of adiponectin. In obese patients, circulating adiponectin levels are reduced and this may be associated with the increased risk of developing immunological, metabolic, and neoplastic diseases including gastric, colon, prostate, cervix, breast, leukemia, and renal cell carcinoma [7, 9–11].

The pathological features of colorectal tumor are affected by plasma concentrations of adiponectin [12]. The mechanism of tumor suppression by adiponectin is not fully understood yet; however, reports indicate that adiponectin can inhibit the expression of endothelial adhesion molecules, angiogenesis, and hematopoiesis [7]. Adiponectin also inhibited cell growth and induced apoptosis in a dose-dependent manner, both in vivo and in vitro [13]. CRC cell lines treated with adiponectin showed a decrease in phosphorylation of PI3K and Akt. Treating CRC cell lines with adiponectin led to activation of AMPK and suppression of mTOR pathway thus inhibition of cancer cell growth. Moreover, knockdown of adiponectin receptors revealed that adiponectin has a suppressive effect on the proliferation of colon cancer cells [14, 15]. Through the use of knockout mice lacking adiponectin, increased intestinal polyp formation is observed [16–18]. In a study on Japanese patients, it was shown that decreased levels of circulating adiponectin were correlated with an increase in colonic adenomas [19]. In another study, Otani et al. in 2009 investigated the effects of exogenous administration of adiponectin on intestinal polyp formation in mice with an adiponectin gene point mutation to determine the role of adiponectin in colorectal carcinogenesis. Adiponectin inhibited colorectal adenoma growth in the mentioned mice [20]. This evidence reveals that adiponectin plays a suppressive role in the development of different cancer types and links obesity to carcinogenesis.

Okada-Iwabu et al. published the discovery of orally active, synthetic small-molecule, which both binds and activates adiponectin receptors 1 and 2. They examined the effect of AdipoRon on insulin resistance, type 2 diabetes, and longevity in obese diabetic mouse models. They observed similar effects to adiponectin via AMPK pathway activation with induction of AMPK phosphorylation and peroxisome proliferator-activated receptor alpha (PPAR-α) activation in muscle and the liver. Their survey results demonstrated improvements in insulin resistance and glucose intolerance, and also, lower plasma glucose, increase in fatty acid oxidation, oxidative stress reduction, increase in shortened life expectancy, and decrease in expression of proinflammatory cytokines coding genes such as tumor necrosis factor alpha (TNF-α) were observed [13].

Recently, another study was done to understand the effect of AdipoRon on post-ischemic myocardial apoptosis using mouse models. The results showed that oral administration of AdipoRon to wild-type mice enhanced cardiac function and attenuated post-ischemic cardiac injury. Furthermore, through AdipoRon treatment, myocardial ischemia/reperfusion (MI/R)-induced apoptotic cell death showed remarkable improvement in mice deficient of either adiponectin knockout (APNKO) or cardiomyocyte-specific AMPK dominant negative (AMPK-DN) [21].

Conclusion

Altogether, these studies suggest that adiponectin functions as a suppressive factor at an early step of colorectal carcinogenesis and may have positive effects in the prevention of obesity-related CRC. Because of difficulties in converting adiponectin to a viable drug form, the application of adiponectin receptor agonist is proposed. The similar effects of AdipoRon to adiponectin have been described in a recent study. No study to date has examined the effect of AdipoRon on CRC cell proliferation. Thus, if the results confirm our hypothesis, the adiponectin receptor agonist, AdipoRon, may be a proper choice in obesity-related CRC chemoprevention.