Adiponectin-activated AMPK stimulates dephosphorylation of AKT through protein phosphatase 2A activation.
ABSTRACT 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.
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ABSTRACT: The increasing percentage of obese individuals in the population and its independent association of increased risk for the development of cancer have heightened the necessity to understand the molecular mechanisms that underlie this connection. The deregulation of adipokines in the setting of obesity and their impact on cancer progression and metastasis is one such area of research. Adipokines are bioactive proteins that mediate metabolism, inflammation, angiogenesis, and proliferation. Altered levels of adipokines or their cognate receptors in cancers can ultimately lead to an imbalance in downstream molecular pathways. Discovery of adipokine receptors in various cancers has highlighted the potential for novel therapeutic targets. Leptin and adiponectin represent two adipokines that elicit generally opposing molecular effects. Epidemiological studies have highlighted associations between increased serum leptin levels and increased tumor growth, while adiponectin exhibits an inverse correlation with cancer development. This review addresses the current level of understanding of molecular pathways activated by adiponectin and leptin to identify areas of intervention and facilitate advancement in the field.Clinical Cancer Research 01/2013; · 7.84 Impact Factor
Article: Diabetes and Cancer.[Show abstract] [Hide abstract]
ABSTRACT: Diabetes is a worldwide health problem that has been increasingly associated with various types of cancers. Epidemiologic studies have shown an increased risk of cancer as well as a higher mortality rate in patients with type 2 diabetes (T2D). The biologic mechanisms driving the link between T2D and cancer are not well understood. In this review, various proposed mechanisms are addressed to explain the relationship between T2D and cancer. Understanding the precise mechanisms that link T2D, obesity, and the metabolic syndrome with cancer will aid in developing treatments that will reduce mortality in individuals with T2D and cancer.Endocrinology and metabolism clinics of North America 03/2014; 43(1):167-185. · 3.56 Impact Factor
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ABSTRACT: Obesity is the cause of a large proportion of breast cancer incidences and mortality in post-menopausal women. In obese people, elevated levels of various growth factors such as insulin and insulin-like growth factors (IGFs) are found. Elevated insulin level leads to increased secretion of estrogen by binding to the circulating sex hormone binding globulin (SHBG). The increased estrogen-mediated downstream signaling favors breast carcinogenesis. Obesity leads to altered expression profiles of various adipokines and cytokines including leptin, adiponectin, IL-6, TNF-α and IL-1β. The increased levels of leptin and decreased adiponectin secretion are directly associated with breast cancer development. Increased levels of pro-inflammatory cytokines within the tumor microenvironment promote tumor development. Efficacy of available breast cancer drugs against obesity-associated breast cancer is yet to be confirmed. In this review, we will discuss different adipokine- and cytokine-mediated molecular signaling pathways involved in obesity-associated breast cancer, available therapeutic strategies and potential therapeutic targets for obesity-associated breast cancer.Cytokine & growth factor reviews 10/2013; · 6.49 Impact Factor