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The Kaposi's sarcoma-associated herpesvirus E3 ubiquitin ligase K5 acts as a novel oncogene, altering cellular metabolism and signaling: implications for tumorigenesis

The Kaposi's sarcoma-associated herpesvirus E3 ubiquitin ligase K5 acts as a novel oncogene,... Karki et al. Infectious Agents and Cancer 2010, 5(Suppl 1):A79 http://www.infectagentscancer.com/content/5/S1/A79 MEETING ABSTRACTS Open Access The Kaposi’s sarcoma-associated herpesvirus E3 ubiquitin ligase K5 acts as a novel oncogene, altering cellular metabolism and signaling: implications for tumorigenesis Roshan Karki, Sabine M Lang, Robert E Means th From 12 International Conference on Malignancies in AIDS and Other Acquired Immunodeficiencies (ICMAOI) Bethesda, MD, USA. 26-27 April, 2010 While it is clear that Kaposi’s sarcoma-associated her- RTK array demonstrated increased activation of the Flt- pesvirus (KSHV or HHV-8) is the causative agent of a 3, Axl, PDGFR-ß, and Flt-4 receptors in K5-expressing number of malignancies including multicentric Castle- versus vector cell lines. Subsequent testing demonstrated man’s disease, primary effusion lymphoma, and Kaposi’s increased sensitivity of K5-expressing THP-1 cells to sarcoma (KS), the molecular mechanisms of tumor growth arrest and apoptosis by sunitinib and increased induction by this virus are still unclear. In part, KS ligand-dependent signaling. Dynamin inhibitor studies lesion presentation is thought to be driven primarily showed that K5 can target these RTKs from the surface through paracrine mechanisms and is mainly observed to increase intracellular signaling. Additional molecular in immunocompromised patients. Monocyte subsets, details will be presented. including dendritic cells and macrophages, are crucial to Overall, our studies demonstrate that the KSHV K5 immune system functionality and are also skewed in KS protein is acting as a novel oncogene – the first viral patients. The goals of this study were to investigate a protein of its kind – to drive monocyte subset expansion potential role for the E3 ubiquitin ligase K5 of KSHV, and alter cellular metabolism, contributing to a pro- which plays a role in viral immune evasion, in altering tumorigenic microenvironment. Intriguingly, the meta- monocyte functionality, thereby contributing to KSHV- bolic changes observed are caused by a single KSHV driven tumorigenesis. protein and thus serve as a useful model to study differ- A series of wild-type (WT) and mutant K5-expressing ent aspects of KS pathology and its overall regulation of stable cell lines were generated in THP-1 monocytic cell cellular metabolism. These studies also provide addi- line and examined. Surprisingly, these cells demon- tional rationale for the currently ongoing clinical trials strated a serum-dependent increased growth rate and a of sunitinib, Gleevec, and rapamycin for the treatment propensity to acidify the growth medium as compared of KSHV-driven neoplasias. Finally, the ability of this to vector-THP-1 cells. Biochemical examination indi- viral E3 ubiquitin ligase to drive metabolic changes pro- cated that K5 induced aerobic glycolysis and other hall- vides the tantalizing suggestion that a cellular ligase may marks of the “Warburg Effect,” including increased be acting in a similar, either physiologic or oncogenic, lactate production and glucose uptake. Observed manner. increases in Akt and total cellular tyrosine phosphoryla- tion, combined with the serum-dependence, suggested a Acknowledgements role for receptor tyrosine kinases (RTKs). A human- This article has been published as part of Infectious Agents and Cancer th Volume 5 Supplement 1, 2010: Proceedings of the 12 International Conference on Malignancies in AIDS and Other Acquired *Correspondence: robert.means@yale.edu Department of Pathology, Yale University School of Medicine, New Haven, CT, USA Full list of author information is available at the end of the article © 2010 Means et al; licensee BioMed Central Ltd. Karki et al. Infectious Agents and Cancer 2010, 5(Suppl 1):A79 Page 2 of 2 http://www.infectagentscancer.com/content/5/S1/A79 Immunodeficiencies (ICMAOI). The full contents of the supplement are available online at http://www.biomedcentral.com/1750-9378/5?issue=S1. Published: 11 October 2010 doi:10.1186/1750-9378-5-S1-A79 Cite this article as: Karki et al.: The Kaposi’s sarcoma-associated herpesvirus E3 ubiquitin ligase K5 acts as a novel oncogene, altering cellular metabolism and signaling: implications for tumorigenesis. Infectious Agents and Cancer 2010 5(Suppl 1):A79. Submit your next manuscript to BioMed Central and take full advantage of: • Convenient online submission • Thorough peer review • No space constraints or color figure charges • Immediate publication on acceptance • Inclusion in PubMed, CAS, Scopus and Google Scholar • Research which is freely available for redistribution Submit your manuscript at www.biomedcentral.com/submit http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Infectious Agents and Cancer Springer Journals

The Kaposi's sarcoma-associated herpesvirus E3 ubiquitin ligase K5 acts as a novel oncogene, altering cellular metabolism and signaling: implications for tumorigenesis

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Publisher
Springer Journals
Copyright
Copyright © 2010 by Means et al; licensee BioMed Central Ltd.
Subject
Biomedicine; Cancer Research; Infectious Diseases; Oncology
eISSN
1750-9378
DOI
10.1186/1750-9378-5-S1-A79
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Abstract

Karki et al. Infectious Agents and Cancer 2010, 5(Suppl 1):A79 http://www.infectagentscancer.com/content/5/S1/A79 MEETING ABSTRACTS Open Access The Kaposi’s sarcoma-associated herpesvirus E3 ubiquitin ligase K5 acts as a novel oncogene, altering cellular metabolism and signaling: implications for tumorigenesis Roshan Karki, Sabine M Lang, Robert E Means th From 12 International Conference on Malignancies in AIDS and Other Acquired Immunodeficiencies (ICMAOI) Bethesda, MD, USA. 26-27 April, 2010 While it is clear that Kaposi’s sarcoma-associated her- RTK array demonstrated increased activation of the Flt- pesvirus (KSHV or HHV-8) is the causative agent of a 3, Axl, PDGFR-ß, and Flt-4 receptors in K5-expressing number of malignancies including multicentric Castle- versus vector cell lines. Subsequent testing demonstrated man’s disease, primary effusion lymphoma, and Kaposi’s increased sensitivity of K5-expressing THP-1 cells to sarcoma (KS), the molecular mechanisms of tumor growth arrest and apoptosis by sunitinib and increased induction by this virus are still unclear. In part, KS ligand-dependent signaling. Dynamin inhibitor studies lesion presentation is thought to be driven primarily showed that K5 can target these RTKs from the surface through paracrine mechanisms and is mainly observed to increase intracellular signaling. Additional molecular in immunocompromised patients. Monocyte subsets, details will be presented. including dendritic cells and macrophages, are crucial to Overall, our studies demonstrate that the KSHV K5 immune system functionality and are also skewed in KS protein is acting as a novel oncogene – the first viral patients. The goals of this study were to investigate a protein of its kind – to drive monocyte subset expansion potential role for the E3 ubiquitin ligase K5 of KSHV, and alter cellular metabolism, contributing to a pro- which plays a role in viral immune evasion, in altering tumorigenic microenvironment. Intriguingly, the meta- monocyte functionality, thereby contributing to KSHV- bolic changes observed are caused by a single KSHV driven tumorigenesis. protein and thus serve as a useful model to study differ- A series of wild-type (WT) and mutant K5-expressing ent aspects of KS pathology and its overall regulation of stable cell lines were generated in THP-1 monocytic cell cellular metabolism. These studies also provide addi- line and examined. Surprisingly, these cells demon- tional rationale for the currently ongoing clinical trials strated a serum-dependent increased growth rate and a of sunitinib, Gleevec, and rapamycin for the treatment propensity to acidify the growth medium as compared of KSHV-driven neoplasias. Finally, the ability of this to vector-THP-1 cells. Biochemical examination indi- viral E3 ubiquitin ligase to drive metabolic changes pro- cated that K5 induced aerobic glycolysis and other hall- vides the tantalizing suggestion that a cellular ligase may marks of the “Warburg Effect,” including increased be acting in a similar, either physiologic or oncogenic, lactate production and glucose uptake. Observed manner. increases in Akt and total cellular tyrosine phosphoryla- tion, combined with the serum-dependence, suggested a Acknowledgements role for receptor tyrosine kinases (RTKs). A human- This article has been published as part of Infectious Agents and Cancer th Volume 5 Supplement 1, 2010: Proceedings of the 12 International Conference on Malignancies in AIDS and Other Acquired *Correspondence: robert.means@yale.edu Department of Pathology, Yale University School of Medicine, New Haven, CT, USA Full list of author information is available at the end of the article © 2010 Means et al; licensee BioMed Central Ltd. Karki et al. Infectious Agents and Cancer 2010, 5(Suppl 1):A79 Page 2 of 2 http://www.infectagentscancer.com/content/5/S1/A79 Immunodeficiencies (ICMAOI). The full contents of the supplement are available online at http://www.biomedcentral.com/1750-9378/5?issue=S1. Published: 11 October 2010 doi:10.1186/1750-9378-5-S1-A79 Cite this article as: Karki et al.: The Kaposi’s sarcoma-associated herpesvirus E3 ubiquitin ligase K5 acts as a novel oncogene, altering cellular metabolism and signaling: implications for tumorigenesis. Infectious Agents and Cancer 2010 5(Suppl 1):A79. Submit your next manuscript to BioMed Central and take full advantage of: • Convenient online submission • Thorough peer review • No space constraints or color figure charges • Immediate publication on acceptance • Inclusion in PubMed, CAS, Scopus and Google Scholar • Research which is freely available for redistribution Submit your manuscript at www.biomedcentral.com/submit

Journal

Infectious Agents and Cancer – Springer Journals

Published: Oct 11, 2010

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