The human body harbors an enormous number of microbiota that influence cancer susceptibility, in part, via their prodigious metabolic capacity and their profound influence on immune cell function. Microbial pathogens drive tumorigenesis in 15–20% of cancer cases. An even larger number of malignancies are associated with an altered composition of commensal microbiota (dysbiosis) based on microbiome studies utilizing metagenomic sequencing. Although association studies cannot distinguish whether changes in microbiota are causes or effects of cancer, a causative role is supported by rigorously controlled pre-clinical studies utilizing gnotobiotic mouse models colonized with one or more specific bacteria. These studies demonstrate that microbiota can alter cancer susceptibility and progression by diverse mechanisms such as modulating inflammation, inducing DNA damage, and producing metabolites involved in oncogenesis or tumor suppression. Evidence is emerging that microbiota can be manipulated for improving cancer treatment. By incorporating probiotics as adjuvants for checkpoint immunotherapy or by designing small molecules that target microbial enzymes, microbiota can be harnessed to improve cancer care.
SUMMARY Microbiome-encoded β-glucuronidase (GUS) enzymes play important roles in human health by metabolizing drugs in the gastrointestinal (GI) tract. The numbers, types and diversity of these proteins in the human GI microbiome, however, remain undefined. We present an atlas of GUS enzymes comprehensive for the Human Microbiome Project GI database. We identify 3,013 total and 279 unique microbiome-encoded GUS proteins clustered into six unique structural categories. We assign their taxonomy, assess cellular localization, reveal the inter-individual variability within the 139 individuals sampled, and discover 112 novel microbial GUS enzymes. A representative in vitro panel of the most common GUS proteins by read abundances highlights structural and functional variabilities within the family, including their differential processing of smaller glucuronides and larger carbohydrates. These data provide a sequencing-to-molecular roadmap for examining microbiome-encoded enzymes essential to human health.
The metabolic differences between B-NHL and primary human B cells are poorly understood. Among human B-cell non-Hodgkin lymphomas (B-NHL), primary effusion lymphoma (PEL) is a unique subset that is linked to infection with Kaposi's sarcoma-associated herpesvirus (KSHV). We report that the metabolic profiles of primary B cells are significantly different from that of PEL. Compared with primary B cells, both aerobic glycolysis and fatty acid synthesis (FAS) are up-regulated in PEL and other types of nonviral B-NHL. We found that aerobic glycolysis and FAS occur in a PI3K-dependent manner and appear to be interdependent. PEL overexpress the fatty acid synthesizing enzyme, FASN, and both PEL and other B-NHL were much more sensitive to the FAS inhibitor, C75, than primary B cells. Our findings suggest that FASN may be a unique candidate for molecular targeted therapy against PEL and other B-NHL.
Primary effusion lymphoma (PEL) constitutes a subset of non-Hodgkin lymphoma whose incidence is highly increased in the context of HIV infection. Kaposi sarcomaassociated herpesvirus is the causative agent of PEL. The phosphatidylinositol 3-kinase (PI3K) signaling pathway plays a critical role in cell proliferation and survival, and this pathway is dysregulated in many different cancers, including PEL, which display activated PI3K, Akt, and mammalian target of rapamycin (mTOR) kinases. PELs rely heavily on PI3K/Akt/mTOR signaling, are dependent on autocrine and paracrine growth factors, and also have a poor prognosis with reported median survival times of less than 6 months. We compared different compounds that inhibit the PI3K/Akt/mTOR pathway in PEL. Although compounds that modulated activity of only a single pathway member inhibited PEL proliferation, the use of a novel compound, NVP-BEZ235, that dually inhibits both PI3K and mTOR kinases was significantly more efficacious in culture and in a PEL xenograft tumor model. NVP-BEZ235 was effective at low nanomolar concentrations and has oral bioavailability. We also report a novel mechanism for NVP-BEZ235 involving the suppression of multiple autocrine and paracrine growth factors required for lymphoma survival. IntroductionThe phosphatidylinositol 3-kinase (PI3K) signaling pathway plays a critical role in cell proliferation and cell survival. PI3K activation stimulates the production of phosphatidylinositol 3,4,5-triphosphate, which results in activation of the kinases PDK1 and Akt. The lipid phosphatase and tensin homolog deleted on chromosome 10 (PTEN) protein is a negative regulator of this pathway. Akt kinase promotes cell survival by phosphorylating, and thereby inactivating, proapoptotic factors, such as the FOXO transcription factor family, GSK-3, caspase-9, and Bad. [1][2][3][4] Phosphorylation of Bad and the FOXO transactivators prevent apoptosis. Akt also phosphorylates p27, a negative regulator of the cell cycle, thereby preventing cell cycle arrest. In addition, Akt activation leads to phosphorylation and activation of the mammalian target of rapamycin (mTOR), a kinase that stimulates protein synthesis and cell proliferation.Activated mTOR protein can associate with raptor and mLST8/GL to form the mTORC1 complex. The mTORC1 complex induces phosphorylation of p70 S6 kinase (S6K), leading to phosphorylation and activation of the ribosomal protein S6. mTORC1 also inhibits 4E-BP1, a repressor of eukaryotic initiation factor eIF4E. This arm of the mTOR pathway is rapamycin-sensitive. In contrast, the mTORC2 complex, which consists of mTOR, mLST8/GL, mSin1, and Rictor, is insensitive to the effects of rapamycin. mTORC2 functions in a feedback loop that phosphorylates and activates Akt by phosphorylation at Ser473. 5 Hence, inhibitors of PI3K/Akt probably have broader effects than mTOR inhibitors.The nutrient sensor, AMP activated kinase (AMPK), is a negative regulator of mTORC1. 6 AMPK controls cellular homeostasis by regulating energy production withi...
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