Suzuki Michio, Takeda Tadashi, Nakagawa Hikaru, Iwata Seiko, Watanabe Takahiro, Siddiquey Mohammed N A, Goshima Fumi, Murata Takayuki, Kawada Jun-Ichi, Ito Yoshinori, Kojima Seiji, Kimura Hiroshi
Department of Pediatrics, Nagoya University Graduate School of Medicine Nagoya, Japan ; Department of Virology, Nagoya University Graduate School of Medicine Nagoya, Japan.
Department of Virology, Nagoya University Graduate School of Medicine Nagoya, Japan.
Front Microbiol. 2015 Apr 9;6:280. doi: 10.3389/fmicb.2015.00280. eCollection 2015.
Epstein-Barr virus (EBV), which infects not only B cells but also T and natural killer (NK) cells, is associated with a variety of lymphoid malignancies. Because EBV-associated T and NK cell lymphomas are refractory and resistant to conventional chemotherapy, there is a continuing need for new effective therapies. EBV-encoded "latent membrane protein 1" (LMP1) is a major oncogene that activates nuclear factor kappa B (NF-κB), c-Jun N-terminal kinase (JNK), and phosphatidylinositol 3-kinase signaling pathways, thus promoting cell growth and inhibiting apoptosis. Recently, we screened a library of small-molecule inhibitors and isolated heat shock protein 90 (Hsp90) inhibitors as candidate suppressors of LMP1 expression. In this study, we evaluated the effects of BIIB021, a synthetic Hsp90 inhibitor, against EBV-positive and -negative T and NK lymphoma cell lines. BIIB021 decreased the expression of LMP1 and its downstream signaling proteins, NF-κB, JNK, and Akt, in EBV-positive cell lines. Treatment with BIIB021 suppressed proliferation in multiple cell lines, although there was no difference between the EBV-positive and -negative lines. BIIB021 also induced apoptosis and arrested the cell cycle at G1 or G2. Further, it down-regulated the protein levels of CDK1, CDK2, and cyclin D3. Finally, we evaluated the in vivo effects of the drug; BIIB021 inhibited the growth of EBV-positive NK cell lymphomas in a murine xenograft model. These results suggest that BIIB021 has suppressive effects against T and NK lymphoma cells through the induction of apoptosis or a cell cycle arrest. Moreover, BIIB021 might help to suppress EBV-positive T or NK cell lymphomas via the down-regulation of LMP1 expression.
爱泼斯坦-巴尔病毒（EBV）不仅感染B细胞，还感染T细胞和自然杀伤（NK）细胞，与多种淋巴系统恶性肿瘤相关。由于EBV相关的T和NK细胞淋巴瘤对传统化疗难治且耐药，因此持续需要新的有效治疗方法。EBV编码的“潜伏膜蛋白1”（LMP1）是一种主要癌基因，可激活核因子κB（NF-κB）、c-Jun氨基末端激酶（JNK）和磷脂酰肌醇3激酶信号通路，从而促进细胞生长并抑制细胞凋亡。最近，我们筛选了一个小分子抑制剂文库，并分离出热休克蛋白90（Hsp90）抑制剂作为LMP1表达的候选抑制剂。在本研究中，我们评估了一种合成的Hsp90抑制剂BIIB021对EBV阳性和阴性T和NK淋巴瘤细胞系的作用。BIIB021降低了EBV阳性细胞系中LMP1及其下游信号蛋白NF-κB、JNK和Akt的表达。用BIIB021处理可抑制多个细胞系的增殖，尽管EBV阳性和阴性细胞系之间没有差异。BIIB021还诱导细胞凋亡并使细胞周期停滞在G1或G2期。此外，它下调了CDK1、CDK2和细胞周期蛋白D3的蛋白水平。最后，我们评估了该药物的体内作用；BIIB021在小鼠异种移植模型中抑制了EBV阳性NK细胞淋巴瘤的生长。这些结果表明，BIIB021通过诱导细胞凋亡或细胞周期停滞对T和NK淋巴瘤细胞具有抑制作用。此外，BIIB021可能通过下调LMP1表达有助于抑制EBV阳性T或NK细胞淋巴瘤。
