Low serum levels of adiponectin are a high risk factor for various types of cancer. Although adiponectin inhibits proliferation and metastasis of breast cancer cells, the underlying molecular mechanisms remain obscure. In this study, we show that adiponectin-activated AMPK reduces the invasiveness of MDA-MB-231 cells by stimulating dephosphorylation of AKT by increasing protein phosphatase 2A (PP2A) activity. Among the various regulatory B56 subunits, B56gamma was directly phosphorylated by AMPK at Ser(298) and Ser(336), leading to an increase of PP2A activity through dephosphorylation of PP2Ac at Tyr(307). We also show that both the blood levels of adiponectin and the tissue levels of PP2A activity were decreased in breast cancer patients and that the direct administration of adiponectin into tumor tissues stimulates PP2A activity. Taken together, these findings show that adiponectin, derived from adipocytes, negatively regulates the invasiveness of breast cancer cells by activating the tumor suppressor PP2A.
"Adiponectin functions as an insulin sensitizer, and low serum adiponectin reversely correlates with insulin resistance . Moreover, adiponectin can inhibit cell proliferation, invasiveness and angiogenesis in vitro by suppression of estrogen receptor α and vascular endothelium growth factor [30-32]. Serum adiponectin would be a protective factor for endometrial cancer. "
[Show abstract][Hide abstract] ABSTRACT: To investigate the relationship between serum concentrations of leptin or adiponectin, and endometrial carcinoma in Chinese women.
We conducted a case-control study of a total of 516 Chinese women to detect the relationships between serum concentrations of leptin or adiponectin, and endometrial carcinoma in Chinese women. The study subject constituted 206 cases of endometrial cancer and 310 normal controls.
Patients with endometrial carcinoma had higher serum leptin concentrations than controls (28.8±2.2 ug/L vs. 19.8±1.4 ug/L; p<0.001). The adiponectin levels in patients were lower than in controls with borderline statistical significance (2,330.7±180.5 ug/L vs. 2,583.9±147.2 ug/L; p=0.078). Logistic regression analysis confirmed the associations between leptin or adiponectin, and endometrial carcinoma after adjustment for age, body mass index, fasting insulin, serum glucose, cholesterol, triglycerides, and high-density lipoprotein cholesterol (odds ratio for the top tertile vs. the bottom tertile: leptin 2.05; 95% confidence interval [CI], 1.28 to 3.29; p<0.001; adiponectin 0.52; 95% CI, 0.32 to 0.83; p<0.001).
Increased leptin or decreased adiponectin levels are associated with endometrial carcinoma.
"Several previous studies have shown anti-cancer effects of adiponectin in different cell models. Various mechanisms have been reported including inhibition of Akt signalling (Ogunwobi and Beales, 2008a), activation of protein phosphatase 2A (Kim et al., 2009a), activation of 5' AMP-activated kinase (Kim et al., 2009a; Ogunwobi and Beales, 2008a), inhibition of lipogenesis (Kim et al., 2010), regulation of p53 (Dos Santos et al., 2008), induction of Bax and cyclin-dependant kinase inhibitors (Kim et al., 2010) as well as increased SOCS3 expression and enhanced SOCS3 binding to the leptin receptor (Sharma et al., 2010) and because different cell lines, from different tissues with different cell behaviours (proliferation, apoptosis, invasion) have been studied, it is not yet possible to be sure if these represent a co-ordinated signalling "
[Show abstract][Hide abstract] ABSTRACT: Obesity is characterized by hyperleptinaemia and hypoadiponectinaemia and these metabolic abnormalities may contribute to the progression of several obesity-associated cancers including oesophageal adenocarcinoma (OAC). We have examined the effects of leptin and adiponectin on OE33 OAC cells. Leptin stimulated proliferation, invasion and migration and inhibited apoptosis in a STAT3-dependant manner. Leptin-stimulated MMP-2 secretion in a partly STAT3-dependent manner and MMP-9 secretion via a STAT3-independent pathway. Adiponectin inhibited leptin-induced proliferation, migration, invasion, MMP secretion and reduced the anti-apoptotic effects: these effects of adiponectin were ameliorated by both a non-specific tyrosine phosphatase inhibitor and a specific PTP1B inhibitor. Adiponectin reduced leptin-stimulated JAK2 activation and STAT3 transcriptional activity in a PTP1B-sensitive manner and adiponectin increased both PTP1B protein and activity. We conclude that adiponectin restrains leptin-induced signalling and pro-carcinogenic behaviour by inhibiting the early events in leptin-induced signal transduction by activating PTP1B. Relative adiponectin deficiency in obesity may contribute to the promotion of OAC.
"There is now firm evidence that PP2A-B55 plays a crucial role in dephosphorylating CDK1 substrates during the mitotic stages and that PP2A-B56 dephosphorylates PLK1 substrates. In addition to the B55 and B56 regulatory subunits of PP2A, many phosphorylation events caused by various PP2A regulatory subunits during cell cycle progression have been elucidated (50-52). In the near future, the reason for some noted phosphorylations on various PP2A regulatory subunits may be understood in terms of cell cycle regulation. "
[Show abstract][Hide abstract] ABSTRACT: To maintain cellular homeostasis against the demands of the extracellular environment, a precise regulation of kinases and phosphatases is essential. In cell cycle regulation mechanisms, activation of the cyclin-dependent kinase (CDK1) and cyclin B complex (CDK1:cyclin B) causes a remarkable change in protein phosphorylation. Activation of CDK1:cyclin B is regulated by two auto-amplification loops-CDK1:cyclin B activates Cdc25, its own activating phosphatase, and inhibits Wee1, its own inhibiting kinase. Recent biological evidence has revealed that the inhibition of its counteracting phosphatase activity also occurs, and it is parallel to CDK1:cyclin B activation during mitosis. Phosphatase regulation of mitotic kinases and their substrates is essential to ensure that the progression of the cell cycle is ordered. Outlining how the mutual control of kinases and phosphatases governs the localization and timing of cell division will give us a new understanding about cell cycle regulation. [BMB Reports 2013; 46(6): 289-294].
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