Adriamycin Enhances Proteasome-Mediated Generation of the Proapoptotic Processed Form of MAGE-A4 in Hepatoma Cells
Adriamycin Enhances Proteasome-Mediated Generation of the Proapoptotic Processed Form of MAGE-A4 in Hepatoma Cells
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DOI：
10.1159/000334307
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发表时间：
2011-12
期刊：
影响因子：
3.5
通讯作者：
T. Sakurai;M. Kudo;K. Itoh;U. Ryu;H. Higashitsuji;J. Fujita
中科院分区：
文献类型：
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作者：
T. Sakurai;M. Kudo;K. Itoh;U. Ryu;H. Higashitsuji;J. Fujita
背景：黑色素瘤抗原 (MAGE)-A4 经过加工产生具有促凋亡活性的 C 末端片段。在这里，我们证明阿霉素通过激活蛋白酶体促进加工后的 MAGE-A4 的产生。众所周知，蛋白酶体可以防止有毒蛋白质的积累，以维持细胞稳态。方法和结果：用亚致死剂量的阿霉素处理表达 MAGE-A4 的肝癌细胞增加了 MAGE-A4 的加工并使细胞对阿霉素诱导的细胞凋亡敏感。 MAGE-A4 的加工受到蛋白酶体抑制剂 MG115、MG132、lactacystin 和 epoxamicin 的抑制。 MAGE-A4 与 S6 蛋白酶体 ATP 酶共免疫沉淀，并在甘油梯度离心过程中存在于含有蛋白酶体的级分中。与蛋白酶体裂解 MAGE-A4 的观点一致，26S 蛋白酶体、泛素和细胞裂解物对于有效体外裂解 MAGE-A4 是必需的。结论：本研究表明，低剂量的阿霉素会增加蛋白酶体活性，从而维持细胞稳态或导致细胞凋亡，至少在目前条件下，取决于 MAGE-A4 的表达。
Background: Melanoma antigen (MAGE)-A4 is processed to generate a C-terminal fragment with proapoptotic activity. Here we demonstrate that Adriamycin promotes generation of the processed MAGE-A4 by activating the proteasome. The proteasome is known to prevent accumulation of toxic proteins to maintain cellular homeostasis. Methods and Results: Treatment of hepatoma cells expressing MAGE-A4 with a sublethal dose of Adriamycin increased the MAGE-A4 processing and sensitized the cells to Adriamycin-induced apoptosis. The processing of MAGE-A4 was inhibited by the proteasome inhibitors MG115, MG132, lactacystin and epoxamicin. MAGE-A4 was coimmunoprecipitated with the S6 proteasomal ATPase, and present in the fractions containing the proteasome during glycerol gradient centrifugation. Consistent with the notion that the proteasome cleaves MAGE-A4, the 26S proteasome, ubiquitin, and cell lysates were necessary for efficient in vitrocleavage of MAGE-A4. Conclusions: The present study suggests that a low dose of Adriamycin increases the proteasome activity, which either maintains cellular homeostasis or leads to apoptosis depending, at least under the present conditions, on the expression of MAGE-A4.