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AdipoR1 (adiponectin receptor 1) is mainly found in skeletal muscle and has a high affinity for globular adiponectin. AdipoR1 is also one of the receptors for progesterone. Adiponectin is a peptide hormone secreted by fat cells. Adiponectin can inhibit the growth of cells by activating the LKB1-AMPK-S6K/FoxO3A/AKT pathway and the caspase pathway by AdipoR1, or by decreasing cell cycle factors and increasing apoptosis proteins. Adiponectin can also inhibit cell invasion by degrading MMP-2 /9 and inhibiting EMT. Its globular structure promotes disease progression via the MAPK-ERK pathway, activation of autophagy, and inhibition of the immune system. The high molecular weight of adiponectin in the total adiponectin is often the main cause of adiponectin. However, in cancer, the ratio of globular adiponectin to full-length adiponectin may be an important factor in the effects of adiponectin on the disease.
Figure 1. Signalling transduction via adiponectin receptors (AdipoR1 and AdipoR2) activation. (Reverchon, et al. 2014)
AdipoR1 and Breast Cancer
A variety of breast cancer cell lines express AdipoR1 and AdipoR2. When adiponectin analogues (ADP355, whose active site is at the globular end of adiponectin) were treated, the activity of ADP355 was reduced by about 52% when inhibiting about 60% of AdipoR1 expression in MCF-7 cells. When 90% of AdipoR2 was inhibited, its activity was only reduced by 20%. This suggests that AdipoR1 may be more important in the role of adiponectin in cells.
After knocking out AdipoR1, the inhibitory cell proliferation caused by adiponectin disappeared. Further experiments demonstrated that this was achieved by adiponectin activating AMPK via AdipoR1 and inhibiting phosphorylation of ERK1 /2. Using high-fat food to culture S-D rats containing MCF-7 cell xenografts, it was found that AdipoR1 overexpression can not only reduce the obesity caused by high-fat diet but also increase the proportion of tumor cells staying in G0 phase and alleviate the increases of tumors volume. AdipoR1 not only appears in epithelial cells but also in stromal cells, indicating that adiponectin not only affects cell growth and proliferation through AdipoR1, but also acts on stromal cells to alter the aggressiveness of breast cancer.
AdipoR1 and Immune Escape Mechanism
Immune escape is a fundamental feature of cancer. The interaction of dendritic cells (DCs) with T cells is expressed in key parts of drug-resistant tumor antigens. Tan et al. found that zinc finger protein A20, B cell lymphokine 3 and tumor necrosis factor receptor associated factor 1 (TRAF-1) are potential regulators of NF-κB signaling through DC AdipoR1 / R2 signaling. Advanced breast cancer and metastatic individuals express high levels of adiponectin receptors AdipoR1 and AdipoR2 to isolate DCs, thereby blunt anti-tumor immune mechanisms. Ligand-receptor interactions on DCs revealed that AdipoR1 stimulates interleukin-10 (IL-10) to produce AMP-activated protein kinase (AMPK) and mitogen-activated protein kinase p38 (MAPKp38) pathway. The pathway AdipoR2 alters the inflammatory process by activating cyclooxygenase-2 (COX-2) and proteasome oxide and proliferator activated receptor peroxisome γ(PPARγ).
AdipoR1 upregulates AMPK and MAPKp38 by its conventional pathway, and IL-10 acts in an autocrine manner to promote its downstream signaling pathway activation. Activation of the IL-10 receptor induces STAT3 and the cytokine signaling 3 (SOCS3) pathway, which then makes DC tolerant. Stimulation of these pathways is sufficient to block the activation of NF-κB in DC, thereby attenuating its ability to stimulate antigen-specific T cell responses. The study found that in the AdipoR2 signaling pathway of DC, the COX-2 pathway may be up-regulated by PPARγ, which promotes the inability of exposed T cells.
Blocking the AdipoR1 / R2 signal on DCs can increase the anti-tumor immunity of tumor-specific T cells. Studies that overexpress AdipoR1 or AdipoR2 on murine DCs have shown that AdipoR1/R2 signal transduction in DCs may interfere with the ability of cancer cells to clear T cells in T cell-mediated tumor protection models. Therefore, although patients with advanced breast cancer have low adiponectin concentrations, the expression of APN receptors on their peripheral DCs is greatly enhanced, which ultimately promotes tumor growth. Therefore, research on how to increase anti-tumor immunity by blocking the interaction between APN and its receptors has become a potentially attractive target for anticancer therapy.
AdipoR1 and Diabetes
Insulin negatively regulates mRNA expression levels of AdipoR1 and AdipoR2, which may be achieved by the PI3K pathway in the insulin signaling pathway. The study found that AdipoR1 mRNA increased nearly 2.5-fold in muscles of streptozotocin-induced diabetic mice, but returned to normal levels after administration of insulin, suggesting that insulin inhibits AdipoR1 expression. It has been reported that when the insulin-sensitive myoblasts or pre-adipocytes differentiate into insulin-sensitive myocytes or adipocytes, the expression level of AdipoR is significantly increased. Studies have shown that normal mice have no difference in AdipoR1 mRNA expression levels in islets compared with diet-induced insulin resistance mice. There was no reduction in AdipoR expression in skeletal muscle in obese type 2 diabetic patients compared with lean, healthy individuals. Studies have reported that the insulin sensitizer (pioglitazone) has little effect on the expression of the AdipoR gene in adipose tissue.