It is reported that Adiponectin is able to suppress NF

It is reported that Adiponectin is able to suppress NF-κB pathway, and Bcr-Abl fusion oncoprotein in CML activates NF-κB by stimulating its nuclear translocation and also by enhancing its transactivation function [25], [26]. Therefore, it is tempting to hypothesize that NF-κB pathway might be involved in Adiponectin downregulating Bcr-Abl expression and effect in IMR-K562 cells. It should also be noted that our in vivo study demonstrated that Adiponectin resensitizes imatinib in IMR-K562 xenograft model in mice. We found that administration of Adiponectin by i.p. injection significantly sensitized IMR-K562 BMI-1 inhibitor to imatinib treatment but yet shows no inhibition in both tumors volume and weight by itself only. Moreover, Real-time PCR demonstrated that Adiponectin combined with imatinib significantly inhibited Bcr-Abl mRNA expression level in the xenograft tumors as compared to imatinib alone. The inhibition rate of Bcr-Abl expression was correlated with the dose of Adiponectin. On the other hand, the tumor inhibition rate of Adiponectin plus imatinib treatment are comparable with the sensitive K562 cells xenograft model treated by single imatinib [27], indicating Adiponectin has the potential to completely reverse the imatinib resistance. Notably, all animals survived Adiponectin combined with imatinib treatment without appreciable adverse effects in terms of body weight loss (data not shown) or other signs of toxicity during the treatment in our in vivo study, suggesting that Adiponectin combined with imatinib were well tolerated. In conclusion, we demonstrate that Adiponectin was able to reverse K562 resistance to imatinib in vitro and in vivo. This reversion effect of Adiponectin in imatinib resistance is due to the downregulation of Bcr-Abl expression and effect in AdipoR1 dependent way, whereas AdipoR2 was not involved. Our data to some extent elucidate the mechanism of Adiponectin reversing imatinib resistance that may provide a new and promising approach in imatinib resistance management in CML therapy.
Conflict of interest
Acknowledgments This work was supported by Wenzhou Science & Technology Program (No. Y20130242).
Introduction Adiponectin (AdipoQ, Acrp30, apM1) is an adipose tissue derived hormone of the C1q/TNF-superfamily which is highly abundant in human serum and shows an inverse correlation with body mass index [1]. Adiponectin ameliorates insulin sensitivity and higher adiponectin levels are associated with a lower risk for type 2 diabetes in Whites, East Asians, Asian Indians, African Americans, and Native Americans [2], [3]. Adiponectin circulates as trimer, hexamer and higher-order multimer (HMW) in serum, and isoform-specific effects have been described [4], [5]. The HMW form is the major active form mediating the insulin-sensitizing effects of adiponectin [2], [5], [6]. Impaired multimerization of adiponectin in humans is associated with type 2 diabetes mellitus showing that higher-order multimeric structures are important for the biological function of this adipokine [6]. Globular adiponectin, the globular C1q domain of adiponectin generated by proteolysis of the full-length protein, is also biologically active [7]. However, circulating levels seem to be rather low questioning the biological significance of this protein [8] that may nevertheless be of therapeutical interest. Adiponectin may also form heterooligomers with additional members of the C1q/TNF-related protein (CTRP) family like the recently described CTRP9 [9] but the physiological role of such complexes has not been evaluated so far. Two 7-transmembrane proteins, AdipoR1 and AdipoR2, have been identified to function as adiponectin receptors [10]. Protein sequence alignment reveals that the N-terminal 69 amino acids of AdipoR1 and the 79 aa of AdipoR2 are specific for each receptor whereas the rest of these proteins is highly homologous (80% identity). Initial studies demonstrate that both receptors are integral membrane proteins with an internal N-terminus and an external C-terminus, which is opposite to the topology of G-protein coupled receptors [10]. T-cadherin binds hexameric and HMW adiponectin in endothelial and smooth muscle cells [11], [12]. However, T-cadherin is a glycosylphosphatidylinositol-anchored protein, and therefore, has to interact with a yet not identified transmembrane receptor protein for signal transduction [12].