1.Identification of lipid-phosphatidylserine (PS) as the target of unbiasedly selected cancer specific peptide-peptoid hybrid PPS1.
Desai TJ1, Toombs JE2, Minna JD2,3,4,5, Brekken RA2,3,4,6, Udugamasooriya DG1,7. Oncotarget. 2016 Apr 22. doi: 10.18632/oncotarget.8929. [Epub ahead of print]
Phosphatidylserine (PS) is an anionic phospholipid maintained on the inner-leaflet of the cell membrane and is externalized in malignant cells. We previously launched a careful unbiased selection targeting biomolecules (e.g. protein, lipid or carbohydrate) distinct to cancer cells by exploiting HCC4017 lung cancer and HBEC30KT normal epithelial cells derived from the same patient, identifying HCC4017 specific peptide-peptoid hybrid PPS1. In this current study, we identified PS as the target of PPS1. We validated direct PPS1 binding to PS using ELISA-like assays, lipid dot blot and liposome based binding assays. In addition, PPS1 recognized other negatively charged and cancer specific lipids such as phosphatidic acid, phosphatidylinositol and phosphatidylglycerol. PPS1 did not bind to neutral lipids such as phosphatidylethanolamine found in cancer and phosphatidylcholine and sphingomyelin found in normal cells. Further we found that the dimeric version of PPS1 (PPS1D1) displayed strong cytotoxicity towards lung cancer cell lines that externalize PS, but not normal cells.
2.Spheroid cancer stem cells display reprogrammed metabolism and obtain energy by actively running the tricarboxylic acid (TCA) cycle.
Sato M1, Kawana K1, Adachi K1, Fujimoto A1, Yoshida M1, Nakamura H1, Nishida H1, Inoue T1, Taguchi A1, Takahashi J1, Eguchi S1, Yamashita A1, Tomio K1, Wada-Hiraike O1, Oda K1, Nagamatsu T1, Osuga Y1, Fujii T1. Oncotarget. 2016 Apr 23. doi: 10.18632/oncotarget.8947. [Epub ahead of print]
The Warburg effect is a metabolic hallmark of cancer cells; cancer cells, unlike normal cells, exclusively activate glycolysis, even in the presence of enough oxygen. On the other hand, intratumoral heterogeneity is currently of interest in cancer research, including that involving cancer stem cells (CSCs). In the present study, we attempted to gain an understanding of metabolism in CSCs that is distinct from that in non-CSCs. After forming spheroids from the OVTOKO (ovarian clear cell adenocarcinoma) and SiHa (cervical squamous cell carcinoma) cell lines, the metabolites of these cells were compared with the metabolites of cancer cells that were cultured in adherent plates. A principle components analysis clearly divided their metabolic features. Amino acids that participate in tricarboxylic acid (TCA) cycle reactions, such as serine and glutamine, were significantly increased in the spheroids. Indeed, spheroids from each cell line contained more total adenylates than did their corresponding cells in adherent cultures.
3.Viral protein suppresses oxidative burst and salicylic acid-dependent autophagy and facilitates bacterial growth on virus-infected plants.
Zvereva AS1, Golyaev V1, Turco S1, Gubaeva EG1, Rajeswaran R1, Schepetilnikov MV2, Srour O2, Ryabova LA2, Boller T1, Pooggin MM1. New Phytol. 2016 Apr 27. doi: 10.1111/nph.13967. [Epub ahead of print]
Virus interactions with plant silencing and innate immunity pathways can potentially alter the susceptibility of virus-infected plants to secondary infections with nonviral pathogens. We found that Arabidopsis plants infected with Cauliflower mosaic virus (CaMV) or transgenic for CaMV silencing suppressor P6 exhibit increased susceptibility to Pseudomonas syringae pv. tomato (Pst) and allow robust growth of the Pst mutant hrcC-, which cannot deploy effectors to suppress innate immunity. The impaired antibacterial defense correlated with the suppressed oxidative burst, reduced accumulation of the defense hormone salicylic acid (SA) and diminished SA-dependent autophagy. The viral protein domain required for suppression of these plant defense responses is dispensable for silencing suppression but essential for binding and activation of the plant target-of-rapamycin (TOR) kinase which, in its active state, blocks cellular autophagy and promotes CaMV translation.
4.Hyaluronic acid-conjugated liposome nanoparticles for targeted delivery to CD44 overexpressing glioblastoma cells.
Hayward SL1, Wilson CL1, Kidambi S1,2,3,4,5. Oncotarget. 2016 Apr 22. doi: 10.18632/oncotarget.8926. [Epub ahead of print]
Glioblastoma Multiforme (GBM) is a highly prevalent and deadly brain malignancy characterized by poor prognosis and restricted disease management potential. Despite the success of nanocarrier systems to improve drug/gene therapy for cancer, active targeting specificity remains a major hurdle for GBM. Additionally, since the brain is a multi-cell type organ, there is a critical need to develop an approach to distinguish between GBM cells and healthy brain cells for safe and successful treatment. In this report, we have incorporated hyaluronic acid (HA) as an active targeting ligand for GBM. To do so, we employed HA conjugated liposomes (HALNPs) to study the uptake pathway in key cells in the brain including primary astrocytes, microglia, and human GBM cells. We observed that the HALNPs specifically target GBM cells over other brain cells due to higher expression of CD44 in tumor cells. Furthermore, CD44 driven HALNP uptake into GBM cells resulted in lysosomal evasion and increased efficacy of Doxorubicin, a model anti-neoplastic agent, while the astrocytes and microglia cells exhibited extensive HALNP-lysosome co-localization and decreased antineoplastic potency.