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Schulz T.F.,Hannover Medical School | Santag S.,Hannover Medical School | Jager W.,Hannover Medical School | Karsten C.B.,Hannover Medical School | And 6 more authors.
Oncogene | Year: 2013

Kaposi's Sarcoma Herpesvirus (KSHV) is the causative agent of Kaposi's Sarcoma (KS) and two rare lymphoproliferative disorders, primary effusion lymphoma (PEL) and the plasmablastic variant of multicentric Castleman's disease (MCD). The KSHV latency-associated nuclear antigen-1 (LANA), required for the replication and maintenance of latent viral episomal DNA, is involved in the transcriptional regulation of viral and cellular genes and interacts with different cellular proteins, including the tumour suppressor p53. Here, we report that LANA also recruits the p53-related nuclear transcription factor p73, which influences cellular processes like DNA damage response, cell cycle progression and apoptosis. Both the full-length isoform TAp73α, as well as its dominant negative regulator ΔNp73α, interact with LANA. LANA affects TAp73α stability and sub-nuclear localisation, as well as TAp73α-mediated transcriptional activation of target genes. We observed that the small-molecule inhibitor Nutlin-3, which disrupts the interaction of p53 and p73 with MDM2, induces apoptotic cell death in p53 wild-type, as well as p53-mutant PEL cell lines, suggesting a possible involvement of p73. The small-molecule RETRA, which activates p73 in the context of mutant p53, leads to the induction of apoptosis in p53-mutant PEL cell lines. RNAi-mediated knockdown of p73 confirmed that these effects depend on the presence of the p73 protein. Furthermore, both Nutlin-3 and RETRA disrupt the LANA-p73 interaction in different PEL cell lines. These results suggest that LANA modulates p73 function and that the LANA-p73 interaction may represent a therapeutic target to interfere with the survival of latently KSHV-infected cells. © 2013 Macmillan Publishers Limited. Source

Eriste E.,University of Tartu | Kurrikoff K.,University of Tartu | Suhorutsenko J.,University of Tartu | Oskolkov N.,University of Tartu | And 7 more authors.
Bioconjugate Chemistry | Year: 2013

Gliomas are therapeutically challenging cancers with poor patient prognosis. New drug delivery strategies are needed to achieve a more efficient chemotherapy-based approach against brain tumors. The current paper demonstrates development of a tumor-targeted delivery vector that is based on a cell-penetrating peptide pVEC and a novel glioma-targeting peptide sequence gHo. The unique tumor-homing peptide gHo was identified using in vitro phage display technology. The novel delivery vector, which we designated as gHoPe2, was constructed by a covalent conjugation of pVEC, gHo, and a cargo; the latter could be either a labeling moiety (such as a fluorescent marker) or a cytostatic entity. Using a fluorescent marker, we demonstrate efficient uptake of the vector in glioma cells and selective labeling of glioma xenograft tumors in a mouse model. This is the first time that we know where in vitro phage display has yielded an efficient, in vivo working vector. We also demonstrate antitumor efficacy of the delivery vector gHoPe2 using a well-characterized chemotherapeutic drug doxorubicin. Vectorized doxorubicin proved to be more efficient than the free drug in a mouse glioma xenograft model after systemic administration of the drugs. In conclusion, we have characterized a novel glioma-homing peptide gHo, demonstrated development of a new and potential glioma-targeted drug delivery vector gHoPe2, and demonstrated the general feasibility of the current approach for constructing cell-penetrating peptide-based targeted delivery systems. © 2013 American Chemical Society. Source

Ojala P.M.,University of Helsinki | Ojala P.M.,Foundation for the Finnish Cancer Institute | Ojala P.M.,Imperial College London | Schulz T.F.,Hannover Medical School
Seminars in Cancer Biology | Year: 2014

Kaposi sarcoma (KS), a viral cancer associated to Kaposi sarcoma herpesvirus (KSHV) infection, is currently the most common tumor in men in sub-Saharan Africa. KS is an angiogenic tumor and characterized by the presence of aberrant vascular structures in the lesion. Although our understanding of how KSHV causes the aberrant differentiation of endothelial cells and the typical vascular abnormalities in KS tumors is far from complete, the experimental evidence reviewed here provides a comprehensive description of the role of KSHV in the pathogenesis of this unusual tumor. In contrast to other tumor viruses, whose interference with cellular processes relating to cell cycle, apoptosis and DNA damage may be at the heart of their oncogenic properties, KSHV may cause KS primarily by its ability to engage with the differentiation and function of endothelial cells.Although the intracellular pathways engaged by KSHV in the endothelial cells are being explored as drug targets, a better understanding of the impact of KSHV on endothelial cell differentiation and vasculogenesis is needed before the encouraging findings can form the basis for new targeted therapeutic approaches to KS. © 2014 Elsevier Ltd. Source

Karhemo P.-R.,University of Helsinki | Ravela S.,University of Helsinki | Laakso M.,University of Helsinki | Ritamo I.,Red Cross | And 10 more authors.
Journal of Proteomics | Year: 2012

Details of metastasis, the deadliest aspect of cancer, are unclear. Cell surface proteins play central roles in adhesive contacts between the tumor cell and the stroma during metastasis. We optimized a fast, small-scale isolation of biotinylated cell surface proteins to reveal novel metastasis-associated players from an isogenic pair of human MDA-MB-435 cancer cells with opposite metastatic phenotypes. Isolated proteins were trypsin digested and analyzed using LC-MS/MS followed by quantitation with the Progenesis LC-MS software. Sixteen proteins displayed over twofold expression differences between the metastatic and non-metastatic cells. Interestingly, overexpression of most of them (14/16) in the metastatic cells indicates a gain of novel surface protein profile as compared to the non-metastatic ones. All five validated, differentially expressed proteins showed higher expression in the metastatic cells in culture, and four of these were further validated in vivo. Moreover, we analyzed expression of two of the identified proteins, CD109 and ITGA6 in 3-dimensional cultures of six melanoma cell lines. Both proteins marked the surface of cells derived from melanoma metastasis over cells derived from primary melanoma. The unbiased identification and validation of both known and novel metastasis-associated proteins indicate a reliable approach for the identification of differentially expressed surface proteins. © 2012 Elsevier B.V. Source

Pekkonen P.,University of Helsinki | Jarviluoma A.,University of Helsinki | Zinovkina N.,University of Helsinki | Cvrljevic A.,University of Turku | And 8 more authors.
Cell Cycle | Year: 2014

Kaposi's sarcoma herpesvirus (KSHV)-encoded v-cyclin, a homolog of cellular cyclin D2, activates cellular CDK6, promotes G1-S transition of the cell cycle, induces DNA damage, apoptosis, autophagy and is reported to have oncogenic potential. Here we show that in vivo expression of v-cyclin in the B- and T-cell lymphocyte compartments results in a markedly low survival due to high penetrance of early-onset T-cell lymphoma and pancarditis. The v-cyclin transgenic mice have smaller pre-tumorigenic lymphoid organs, showing decreased cellularity, and increased proliferation and apoptosis. Furthermore, v-cyclin expression resulted in decreased amounts of CD3-expressing mature T-cells in the secondary lymphoid organs concurrent with alterations in the T-cell subpopulations of the thymus. This suggests that v-cyclin interferes with normal T-cell development. As the Notch pathway is recognized for its role in both T-cell development and lymphoma initiation, we addressed the role of Notch in the v-cyclin-induced alterations. Fittingly, we demonstrate induction of Notch3 and Hes1 in the pre-tumorigenic thymi and lymphomas of v-cyclin expressing mice, and show that lymphoma growth and viability are dependent on activated Notch signaling. Notch3 transcription and growth of the lymphomas was dependent on CDK6, as determined by silencing of CDK6 expression or chemical inhibition, respectively. Our work here reveals a viral cyclin-CDK6 complex as an upstream regulator of Notch receptor, suggesting that cyclins can play a role in the initiation of Notch-dependent lymphomagenesis. © 2014 Published with license by Taylor & Francis Group, LLC. Source

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