Niclosamide, an anti-helminthic molecule, downregulates the retroviral oncoprotein Tax and pro-survival Bcl-2 proteins in HTLV-1-transformed T lymphocytes.
Niclosamide, an anti-helminthic molecule, downregulates the retroviral oncoprotein Tax and pro-survival Bcl-2 proteins in HTLV-1-transformed T lymphocytes.
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DOI：
10.1016/j.bbrc.2015.06.120
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发表时间：
2015-08-14
影响因子：
3.1
通讯作者：
Cheng H
中科院分区：
文献类型：
--
作者：
Xiang D;Yuan Y;Chen L;Liu X;Belani C;Cheng H
成人T细胞白血病和淋巴瘤（ATL）是一种高度侵袭性的血液恶性肿瘤，由人类T细胞白血病病毒1型（HTLV-1）慢性感染引起。病毒基因组编码致癌蛋白Tax，其在反式激活病毒基因转录和去调节细胞致癌信号传导以促进病毒感染的T细胞的存活、增殖和转化中起关键作用。因此，Tax是理想的治疗靶点，特别是在HTLV-1介导的肿瘤发生的早期阶段。我们在这里表明，氯硝柳胺，抗蠕虫分子，诱导HTLV-1转化的T细胞凋亡。氯硝柳胺促进Tax蛋白在蛋白酶体中的降解。与氯硝柳胺介导的Tax降解一致，该化合物抑制MAPK/ERK 1/2和I κ B激酶的活性。此外，氯硝柳胺下调Stat3和促生存Bcl-2家族成员如Mcl-1，并通过诱导Tax降解抑制HTLV-1的病毒基因转录。由于Tax、Stat3和Mcl-1是促进HTLV-1转化T细胞存活和生长的关键分子，我们的研究结果证明了氯硝柳胺诱导Tax降解和下调各种细胞促存活分子的新机制，从而促进HTLV-1相关白血病细胞的凋亡。
Adult T cell leukemia and lymphoma (ATL) is a highly aggressive form of hematological malignancy and is caused by chronic infection of human T cell leukemia virus type 1 (HTLV-1). The viral genome encodes an oncogenic protein, Tax, which plays a key role in transactivating viral gene transcription and in deregulating cellular oncogenic signaling to promote survival, proliferation and transformation of virally infected T cells. Hence, Tax is a desirable therapeutic target, particularly at early stage of HTLV-1-mediated oncogenesis. We here show that niclosamide, an anti-helminthic molecule, induced apoptosis of HTLV-1-transformed T cells. Niclosamide facilitated degradation of the Tax protein in proteasome. Consistent with niclosamide-mediated Tax degradation, this compound inhibited activities of MAPK/ERK1/2 and IκB kinases. In addition, niclosamide downregulated Stat3 and pro-survival Bcl-2 family members such as Mcl-1 and repressed the viral gene transcription of HTLV-1 through induction of Tax degradation. Since Tax, Stat3 and Mcl-1 are crucial molecules for promoting survival and growth of HTLV-1-transformed T cells, our findings demonstrate a novel mechanism of niclosamide in inducing Tax degradation and downregulating various cellular pro-survival molecules, thereby promoting apoptosis of HTLV-1-associated leukemia cells.