Alterations in ectopic lipid deposition and circulating lipids are major risk factors for developing cardiometabolic diseases. Angiopoietin-like protein 4 (ANGPTL4), a protein that inhibits lipoprotein lipase (LPL), controls fatty acid (FA) uptake in adipose and oxidative tissues and regulates circulating triacylglycerol-rich (TAG-rich) lipoproteins. Unfortunately, global depletion of ANGPTL4 results in severe metabolic abnormalities, inflammation, and fibrosis when mice are fed a high-fat diet (HFD), limiting our understanding of the contribution of ANGPTL4 in metabolic disorders. Here, we demonstrate that genetic ablation of ANGPTL4 in adipose tissue (AT) results in enhanced LPL activity, rapid clearance of circulating TAGs, increased AT lipolysis and FA oxidation, and decreased FA synthesis in AT. Most importantly, we found that absence of ANGPTL4 in AT prevents excessive ectopic lipid deposition in the liver and muscle, reducing novel PKC (nPKC) membrane translocation and enhancing insulin signaling. As a result, we observed a remarkable improvement in glucose tolerance in short-term HFD-fed AT-specific Angptl4-KO mice. Finally, lack of ANGPTL4 in AT enhances the clearance of proatherogenic lipoproteins, attenuates inflammation, and reduces atherosclerosis. Together, these findings uncovered an essential role of AT ANGPTL4 in regulating peripheral lipid deposition, influencing whole-body lipid and glucose metabolism and the progression of atherosclerosis.

Cancer cells exhibit unique metabolic response and adaptation to the fluctuating microenvironment, yet molecular and biochemical events imprinting this phenomenon are unclear. Here, we show that metabolic homeostasis and adaptation to metabolic stress in cancer cells are primarily achieved by an integrated response exerted by the activation of AMPK. We provide evidence that AMPK-p38-PGC-1α axis, by regulating energy homeostasis, maintains survival in cancer cells under glucose-limiting conditions. Functioning as a molecular switch, AMPK promotes glycolysis by activating PFK2, and facilitates mitochondrial metabolism of non-glucose carbon sources thereby maintaining cellular ATP level. Interestingly, we noted that AMPK can promote oxidative metabolism via increasing mitochondrial biogenesis and OXPHOS capacity via regulating expression of PGC-1α through p38MAPK activation. Taken together, our study signifies the fundamental role of AMPK in controlling cellular bioenergetics and mitochondrial biogenesis in cancer cells.

microRNA-21 (miR-21) is the most commonly upregulated miRNA in solid tumors. This cancer-associated microRNA (oncomiR) regulates various downstream effectors associated with tumor pathogenesis during all stages of carcinogenesis. In this study, we analyzed the function of miR-21 in noncancer cells of the tumor microenvironment to further evaluate its contribution to tumor progression. We report that the expression of miR-21 in cells of the tumor immune infiltrate, and in particular in macrophages, was responsible for promoting tumor growth. Absence of miR-21 expression in tumor- associated macrophages (TAMs), caused a global rewiring of their transcriptional regulatory network that was skewed toward a proinflammatory angiostatic phenotype. This promoted an antitumoral immune response characterized by a macrophage-mediated improvement of cytotoxic T-cell responses through the induction of cytokines and chemokines, including IL-12 and C-X-C motif chemokine 10. These effects translated to a reduction in tumor neovascularization and an induction of tumor cell death that led to decreased tumor growth. Additionally, using the carrier peptide pH (low) insertion peptide, we were able to target miR-21 in TAMs, which decreased tumor growth even under conditions where miR-21 expression was deficient in cancer cells. Consequently, miR-21 inhibition in TAMs induced an angiostatic and immunostimulatory activation with potential therapeutic implications.

BackgroundDespite modern advances in treatment, skin cancer is still one of the most common causes of death in the western countries. Chemotherapy plays an important role in melanoma management. Tamoxifen has been used either alone or in- combination with other chemotherapeutic agents to treat melanoma. However, response rate of tamoxifen as a single agent has been comparatively low. In the present study, we investigated whether treatment with methyl-β-cyclodextrin (MCD), a cholesterol depleting agent, increases the efficacy of tamoxifen in melanoma cells.MethodsThis was a two-part study that incorporated in vitro effects of tamoxifen and MCD combination by analyzing cell survival, apoptosis and cell cycle analysis and in vivo antitumor efficacy on tumor isografts in C57BL/6J mice.ResultsMCD potentiated tamoxifen induced anticancer effects by causing cell cycle arrest and induction of apoptosis. Sensitization to tamoxifen was associated with down regulation of antiapoptotic protein Bcl-2, up-regulation of proapoptotic protein Bax, reduced caveolin-1 (Cav-1) and decreased pAkt/pERK levels. Co-administration of tamoxifen and MCD caused significant reduction in tumor volume and tumor weight in mice due to enhancement of drug uptake in the tumor. Supplementation with cholesterol abrogated combined effect of tamoxifen and MCD.ConclusionOur results emphasize a potential synergistic effect of tamoxifen with MCD, and therefore, may provide a unique therapeutic window for improvement in melanoma treatment.Electronic supplementary materialThe online version of this article (doi:10.1186/1476-4598-13-204) contains supplementary material, which is available to authorized users.