Tumor cells display progressive changes in metabolism that correlate with malignancy, including development of a lipogenic phenotype. How stored fats are liberated and remodeled to support cancer ...pathogenesis, however, remains unknown. Here, we show that the enzyme monoacylglycerol lipase (MAGL) is highly expressed in aggressive human cancer cells and primary tumors, where it regulates a fatty acid network enriched in oncogenic signaling lipids that promotes migration, invasion, survival, and in vivo tumor growth. Overexpression of MAGL in nonaggressive cancer cells recapitulates this fatty acid network and increases their pathogenicity—phenotypes that are reversed by an MAGL inhibitor. Impairments in MAGL-dependent tumor growth are rescued by a high-fat diet, indicating that exogenous sources of fatty acids can contribute to malignancy in cancers lacking MAGL activity. Together, these findings reveal how cancer cells can co-opt a lipolytic enzyme to translate their lipogenic state into an array of protumorigenic signals.
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► Monoacylglycerol lipase (MAGL) is elevated in aggressive human cancer cells ► Loss of MAGL lowers fatty acid levels in cancer cells and impairs pathogenicity ► MAGL controls a signaling network enriched in protumorigenic lipids ► A high-fat diet can restore the growth of tumors lacking MAGL in vivo
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Functional proteomic profiling reveals several brain hydrolase targets for endocannabinoid biosynthesis inhibitors.
The endocannabinoid 2-arachidonoylglycerol (2-AG) has been implicated as a key ...retrograde mediator in the nervous system based on pharmacological studies using inhibitors of the 2-AG biosynthetic enzymes diacyglycerol lipase α and β (DAGL-α/β). Here, we show by competitive activity-based protein profiling that the DAGL-α/β inhibitors, tetrahydrolipstatin (THL) and RHC80267, block several brain serine hydrolases with potencies equal to or greater than their inhibitory activity against DAGL enzymes. Interestingly, a minimal overlap in target profiles was observed for THL and RHC80267, suggesting that pharmacological effects observed with both agents may be viewed as good initial evidence for DAGL-dependent events.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Metalloproteases are a large, diverse class of enzymes involved in many physiological and disease processes. Metalloproteases are regulated by post-translational mechanisms that diminish the ...effectiveness of conventional genomic and proteomic methods for their functional characterization. Chemical probes directed at active sites offer a potential way to measure metalloprotease activities in biological systems; however, large variations in structure limit the scope of any single small-molecule probe aimed at profiling this enzyme class. Here, we address this problem by creating a library of metalloprotease-directed probes that show complementary target selectivity. These probes were applied as a 'cocktail' to proteomes and their labeling profiles were analyzed collectively using an advanced liquid chromatography-mass spectrometry platform. More than 20 metalloproteases were identified, including members from nearly all of the major branches of this enzyme class. These findings suggest that chemical proteomic methods can serve as a universal strategy to profile the activity of the metalloprotease superfamily in complex biological systems.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Bone mineral density loss and fat accumulation are common in people living with HIV. The bone-derived hormone, undercarboxylated osteocalcin (ucOCN) regulates fat metabolism. We investigated the ...relationship between ucOCN change and body fat change among perimenopausal/postmenopausal HIV-seronegative and HIV-seropositive women on long-term antiretrovirals.
Perimenopausal and postmenopausal women enrolled in the Women's Interagency HIV Study MSK substudy underwent trunk and total fat assessment by dual energy x-ray absorptiometry (DXA) at study enrollment (index visit) and again 2 years later. Circulating ucOCN and cOCN were also measured at the index and 2-year visits. The correlation between the 2-year change in ucOCN and cOCN and change in trunk and total fat was assessed as a function of HIV serostatus using linear regression modeling. Multivariate linear regression assessed the association between ucOCN and cOCN change and total and trunk fat change after adjusting for sociodemographic variables. Linear regression models restricted to HIV-seropositive women were performed to examine the contributions of HIV-specific factors (index CD4 count, viral load, and combined antiretroviral therapy use) on the associations.
Increased ucOCN over the 2-year follow-up was associated with less trunk and total fat accumulation in models adjusting for HIV serostatus and participants sociodemographics, whereas there was no association with cOCN and the fat parameters. None of the HIV-specific factors evaluated influenced the association between ucOCN and fat parameters.
The current study suggests that increases in ucOCN are associated with decreased fat accumulation in HIV-seronegative and HIV-seropositive postmenopausal women on long-term antiretroviral therapy.
Climate warming may affect the distribution of helminth parasites, allowing endemic species to increase in prevalence and new species to appear. We analyzed tissues from 141 ice-associated seals ...collected in the Alaskan (US) Bering and Chukchi seas during 2006–15 for internal helminth parasites and compared results with past studies. Specimens were collected from: ringed seals (Pusa hispida), bearded seals (Erignathus barbatus), spotted seals (Phoca largha), and ribbon seals (Histriophoca fasciata). Helminths were present in 94% (133/141) of the seals sampled. Nematodes were most prevalent in bearded (97%, 72/74) and spotted seals (93%, 13/14). Cestodes were most prevalent in bearded seals (82%, 61/74) and absent in ribbon seals, trematodes were only found in bearded (64%, 47/74) and ringed (5%, 2/44) seals, and acanthocephalans were mostly found in ringed (61%, 27/44) and spotted (64%, 9/14) seals. Although no helminths were new to the Bering-Chukchi Seas region, this study found a previously unreported host record for the lungworm Parafilaroides (Filaroides) gymnurus in a ribbon seal. We also found the lungworm Otostrongylus circumlitus in a ribbon seal and P. (F.) gymnurus in bearded seals, representing location records previously unreported from the Bering-Chukchi Seas region (although they have been reported from the Sea of Okhotsk). We found the cestode genus Pyramicocephalus in bearded seals (3%, 2/74) at a lower prevalence than was reported previously for Pyramicocephalus phocarum (44–100%) in the Bering-Chukchi Seas region. We found no species of the acanthocephalan genus Bolbosoma, although the genus was previously identified in ringed, spotted, and ribbon seals. This study yielded no new helminths and no increases in the prevalence of endemic parasites in these seal species.
A significant gap exists between genetics-based investigations of polyketide synthase (PKS) and nonribosomal peptide synthetase (NRPS) biosynthetic pathways and our understanding of their regulation, ...interaction, and activity in living systems. To help bridge this gap, here we present an orthogonal active site identification system (OASIS) for the proteomic identification and analysis of PKS/NRPS biosynthetic enzymes. OASIS probes target conserved features of PKS/NRPS active sites to provide activity-based enrichment of modular synthases, followed by analysis through multidimensional protein identification technology (MudPIT) LC-MS/MS analysis. When applied to the model bacterium Bacillus subtilis, this functional proteomics method detects and quantifies all four modular synthases in the organism. Furthermore, tandem application of multiple OASIS probes enhances identification of specific PKS/NRPS modules from complex proteomic mixtures. By expanding the dynamic range of proteomic analysis for PKS/NRPS enzymes, OASIS offers a valuable tool for strain comparison, culture condition optimization, and enzyme discovery.
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IJS, KILJ, NUK, PNG, UL, UM, UPUK
A study of the structure−activity relationships (SAR) of 2f (OL-135), a potent inhibitor of fatty acid amide hydrolase (FAAH), is detailed, targeting the 5-position of the oxazole. Examination of a ...series of substituted benzene derivatives (12 − 14) revealed that the optimal position for substitution was the meta-position with selected members approaching or exceeding the potency of 2f. Concurrent with these studies, the effect of substitution on the pyridine ring of 2f was also examined. A series of small, nonaromatic C5-substituents was also explored and revealed that the K i follows a well-defined correlation with the Hammett σp constant (ρ = 3.01, R 2 = 0.91) in which electron-withdrawing substituents enhance potency, leading to inhibitors with K is as low as 400 pM (20n). Proteomic-wide screening of the inhibitors revealed that most are exquisitely selective for FAAH over all other mammalian proteases, reversing the 100-fold preference of 20a (C5 substituent = H) for the enzyme TGH.
Estrogen receptor (ER)-negative breast cancer shows a higher incidence in women of African ancestry compared to women of European ancestry. In search of common risk alleles for ER-negative breast ...cancer, we combined genome-wide association study (GWAS) data from women of African ancestry (1,004 ER-negative cases and 2,745 controls) and European ancestry (1,718 ER-negative cases and 3,670 controls), with replication testing conducted in an additional 2,292 ER-negative cases and 16,901 controls of European ancestry. We identified a common risk variant for ER-negative breast cancer at the TERT-CLPTM1L locus on chromosome 5p15 (rs10069690: per-allele odds ratio (OR) = 1.18 per allele, P = 1.0 × 10(-10)). The variant was also significantly associated with triple-negative (ER-negative, progesterone receptor (PR)-negative and human epidermal growth factor-2 (HER2)-negative) breast cancer (OR = 1.25, P = 1.1 × 10(-9)), particularly in younger women (<50 years of age) (OR = 1.48, P = 1.9 × 10(-9)). Our results identify a genetic locus associated with estrogen receptor negative breast cancer subtypes in multiple populations.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Chemical exposures are important risks for development of hepatocellular carcinoma (HCC). One such chemical, diethylnitrosamine (DENA), is present in food products as well as in industrial and ...research settings. Further examination of tumors induced by DENA may yield clues to human risk. HCC from seven rhesus macaques exposed to DENA was selected from a tissue archive to examine for evidence of Wnt/β-catenin signaling events, which are frequently associated with HCC. DENA exposure durations ranged from 8 to 207 months, and total accumulated dose ranged from 0.7 to 4.08 mg. Unexposed colony breeder macaques served as controls. Previously unrecognized HCC metastases were discovered in lungs of three macaques. Overexpression of β-catenin and glutamine synthetase was detected by immunohistochemistry in six confirmed primary HCC and all metastatic HCC, which implicated Wnt/β-catenin activation. Concomitant β-catenin gene mutation was detected in one primary HCC; similar findings have been reported in human and rodent HCC. Neither β-catenin mutation nor β-catenin overexpression appeared to influence metastatic potential. Accumulation of intracellular proteins involved in Wnt/β-catenin signaling during HCC oncogenesis in rhesus macaques exposed to DENA appears to include other mechanisms, in addition to mutation of β-catenin gene.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
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