Adiponectin signals in prostate cancer cells through Akt to activate the mammalian target of rapamycin pathway

Abstract

Adiponectin has received much attention due to its beneficial effects on insulin sensitivity, and epidemiologic studies have further shown an inverse association between adiponectin levels and risk for multiple tumors, which is independent of the IGF system or other risk factors. Previous studies have shown that adiponectin can activate AMP-activated protein kinase (AMPK) in myocytes, hepatocytes, and adipocytes, suggesting that adiponectin may suppress tumor development through AMPK activation and subsequent inhibition of mammalian target of rapamycin (mTOR). However, the mechanisms through which adiponectin affects cancer cells are not understood, and it remains to be determined whether adiponectin is linked to the same downstream targets in all cells types, and in particular in cancer cells. In the present study, we demonstrate that while adiponectin stimulates AMPK in phosphatase and tensin homolog deleted on chromosome ten (PTEN) deficient LNCaP prostate cancer cells, it also increases mTOR activity as assessed by phosphorylation of two downstream targets, p70 S6 kinase and ribosomal protein S6. This adiponectin stimulation of mTOR was mediated through phosphatidylinositol 3-kinase (PI3 kinase) and Akt activation. These results show that adiponectin can activate both AMPK and PI3 kinase/Akt pathways, and that cell type-specific factors such as PTEN status may determine which of these pathways will have the dominant effect on mTOR. Therefore, while it is possible that high endogenous adiponectin levels could be protective against cancer by direct mechanisms or indirect systemic mechanisms, our results indicate that adiponectin may also directly stimulate signaling pathways that enhance the growth of some tumors.

The Effects of Adiponectin and Metformin on Prostate and Colon Neoplasia Involve Activation of AMP-Activated Protein Kinase

“…Our observations are consistent with the expected consequences of AMPK activation, whereas the mechanism underlying the activation of mTOR observed by others remains unclear (26). Furthermore, we observed growth inhibition by adiponectin under our experimental conditions, whereas effects on growth were not reported in the study that used higher adiponectin concentrations.…”

“…In contrast to our observations, a recent study reported unexpected activation of mTOR and S6K in prostate cancer cells exposed to adiponectin (26). The difference in results may be related to important differences in experimental conditions: We used adiponectin at physiologic concentrations, Twenty-four hours after transfection, cells were treated with adiponectin (500 ng/mL) for 72 h. Cell proliferation in each well was measured by Alamar Blue dye reduction.…”

Molecular Mechanisms Linking Adiponectin Receptor Signalling and Cancer

“…Regarding cancer cells, we reported that adiponectin decreased cell proliferation in colorectal cancer cells through activation of AMPK and inhibition of mTOR and consecutive molecules [6]. On the other hand, Barb et al reported that adiponectin activated AMPK but did not inhibit mTOR in prostate cancer cells [85]. Because the effect of adiponectin on the mTOR signaling pathway may be cancer cell type specific, more detailed studies of the role of adiponectin in cancer cells are needed.…”

Cytokines and Metabolic Factors Regulate Tumoricidal T-Cell Function During Cancer Immunotherapy

“…Specifically, activation of inflammatory signaling pathways such as NF-kB and c-Jun N-terminal kinase 1, along with increased IL-1β, TNF and IL-6 have been linked with tumorigenesis [45][46][47]. Second, adipocyte-secreted adiponectin has the potential to influence tumor growth by affecting the mTOR and AMP-activated protein kinase pathways [48,49].…”