title: Sangivamycin induces apoptosis by suppressing Erk signaling in primary effusion lymphoma cells.
abstract: Sangivamycin, a structural analog of adenosine and antibiotic exhibiting antitumor and antivirus activities, inhibits protein kinase C and the synthesis of both DNA and RNA. Primary effusion lymphoma (PEL) is an aggressive neoplasm caused by Kaposi's sarcoma-associated herpesvirus (KSHV) in immunosuppressed patients and HIV-infected homosexual males. PEL cells are derived from post-germinal center B cells, and are infected with KSHV. Herein, we asked if sangivamycin might be useful to treat PEL. We found that sangivamycin killed PEL cells, and we explored the underlying mechanism. Sangivamycin treatment drastically decreased the viability of PEL cell lines compared to KSHV-uninfected B lymphoma cell lines. Sangivamycin induced the apoptosis of PEL cells by activating caspase-7 and -9. Further, sangivamycin suppressed the phosphorylation of Erk1/2 and Akt, thus inhibiting activation of the proteins. Inhibitors of Akt and MEK suppressed the proliferation of PEL cells compared to KSHV-uninfected cells. It is known that activation of Erk and Akt signaling inhibits apoptosis and promotes proliferation in PEL cells. Our data therefore suggest that sangivamycin induces apoptosis by inhibiting Erk and Akt signaling in such cells. We next investigated whether sangivamycin, in combination with an HSP90 inhibitor geldanamycin (GA) or valproate (valproic acid), potentiated the cytotoxic effects of the latter drugs on PEL cells. Compared to treatment with GA or valproate alone, the addition of sangivamycin enhanced cytotoxic activity. Our data thus indicate that sangivamycin may find clinical utility as a novel anti-cancer agent targeting PEL.
authors.affiliation: Department of Biotechnology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Kofu-shi 400-8511, Japan.
authors.forename: Kazufumi
authors.initials: K
authors.lastname: Wakao
authors.affiliation: Department of Cell Biology, Kyoto Pharmaceutical University, Misasagi-Shichonocho 1, Yamashinaku, Kyoto 607-8412, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Department of Biotechnology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Kofu-shi 400-8511, Japan.
authors.forename: Tadatoshi
authors.initials: T
authors.lastname: Takadama
authors.affiliation: Department of Biotechnology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Kofu-shi 400-8511, Japan.
authors.forename: Sadaharu
authors.initials: S
authors.lastname: Ui
authors.affiliation: Department of Cell Biology, Kyoto Pharmaceutical University, Misasagi-Shichonocho 1, Yamashinaku, Kyoto 607-8412, Japan.
authors.forename: Zenpei
authors.initials: Z
authors.lastname: Shigemi
authors.affiliation: Department of Cell Biology, Kyoto Pharmaceutical University, Misasagi-Shichonocho 1, Yamashinaku, Kyoto 607-8412, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kagawa
authors.affiliation: Department of Molecular Cell Biology, Faculty of Medicine, University of Yamanashi, Chuoh-shi 409-3898, Japan.
authors.forename: Chizuka
authors.initials: C
authors.lastname: Higashi
authors.affiliation: Department of Molecular Cell Biology, Faculty of Medicine, University of Yamanashi, Chuoh-shi 409-3898, Japan.
authors.forename: Rie
authors.initials: R
authors.lastname: Ohga
authors.affiliation: Department of Molecular Cell Biology, Faculty of Medicine, University of Yamanashi, Chuoh-shi 409-3898, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Taira
authors.affiliation: Department of Cell Biology, Kyoto Pharmaceutical University, Misasagi-Shichonocho 1, Yamashinaku, Kyoto 607-8412, Japan. Electronic address: fuji2@mb.kyoto-phu.ac.jp.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Fujimuro
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D053179:Caspase 7 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015967:Gene Expression Regulation, Viral; D019288:Herpesvirus 8, Human / Q000235:genetics / Q000502:physiology; D054884:Host-Pathogen Interactions; D006801:Humans; D054685:Lymphoma, Primary Effusion / Q000378:metabolism / Q000473:pathology / Q000821:virology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011741:Pyrimidine Nucleosides / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D011741:Pyrimidine Nucleosides; C005699:sangivamycin; D011065:Poly(ADP-ribose) Polymerases; D051057:Proto-Oncogene Proteins c-akt; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D053179:Caspase 7; D053453:Caspase 9
keywords: Akt; Apoptosis; Erk; KSHV; Primary effusion lymphoma; Sangivamycin