Sangivamycin induces apoptosis by suppressing Erk signaling in primary effusion lymphoma cells.
Sangivamycin induces apoptosis by suppressing Erk signaling in primary effusion lymphoma cells.
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DOI：
10.1016/j.bbrc.2014.01.017
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发表时间：
2014-02
影响因子：
3.1
通讯作者：
Kazufumi Wakao;Tadashi Watanabe;Tadatoshi Takadama;S. Ui;Zenpei Shigemi;Hiroki Kagawa;Chizuka Higashi-Chizuka-H
中科院分区：
文献类型：
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作者：
Kazufumi Wakao;Tadashi Watanabe;Tadatoshi Takadama;S. Ui;Zenpei Shigemi;Hiroki Kagawa;Chizuka Higashi-Chizuka-H
桑伐霉素是腺苷的结构类似物和抗生素，具有抗肿瘤和抗病毒活性，抑制蛋白激酶C以及DNA和RNA的合成。原发性渗出性淋巴瘤（PEL）是由卡波西肉瘤相关疱疹病毒（KSHV）在免疫抑制患者和HIV感染的同性恋男性中引起的侵袭性肿瘤。PEL细胞来源于生发后中心B细胞，并被KSHV感染。在此，我们询问桑戈霉素是否可用于治疗PEL。我们发现桑戈霉素杀死了PEL细胞，并探讨了其潜在的机制。与KSHV未感染的B淋巴瘤细胞系相比，桑戈霉素处理显著降低了PEL细胞系的活力。Sangivamycin通过激活caspase-7和caspase-9诱导PEL细胞凋亡。此外，桑伐霉素抑制Erk 1/2和Akt的磷酸化，从而抑制蛋白质的活化。Akt和MEK的抑制剂抑制了与KSHV未感染的细胞相比的PEL细胞的增殖。已知Erk和Akt信号传导的激活抑制PEL细胞中的凋亡并促进增殖。因此，我们的数据表明，桑伐霉素诱导细胞凋亡，抑制Erk和Akt信号在这样的细胞。接下来，我们研究了桑伐霉素与HSP 90抑制剂格尔德霉素（GA）或丙戊酸盐（丙戊酸）组合是否增强了后者药物对PEL细胞的细胞毒性作用。与单独使用GA或丙戊酸盐的治疗相比，添加桑伐霉素增强了细胞毒活性。因此，我们的数据表明，桑戈霉素可能会发现作为一种新的抗癌剂靶向PEL的临床效用。
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.