The stress granule protein Vgl1 and poly(A)-binding protein Pab1 are required for doxorubicin resistance in fission yeast Schizosaccharomyces pombe
The stress granule protein Vgl1 and poly(A)-binding protein Pab1 are required for doxorubicin resistance in fission yeast Schizosaccharomyces pombe
复制标题
裂殖酵母裂殖酵母中的阿霉素抗性需要应激颗粒蛋白 Vgl1 和多聚腺苷酸结合蛋白 Pab1
DOI：
10.1016/j.bbrc.2011.11.127
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发表时间：
2012
影响因子：
3.1
通讯作者：
Takahiro Morita
中科院分区：
文献类型：
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作者：
Takahiro Morita
阿霉素是一种蒽环类抗生素，广泛用于化疗。虽然阿霉素在治疗包括实体瘤和白血病在内的几种癌症中是有效的，但其作用机制的基础还不完全清楚。在这里，我们描述了阿霉素的影响和它的关系与应力颗粒形成的裂殖酵母，裂殖酵母。我们发现，破坏编码应激颗粒组分的基因，包括编码多KH型RNA结合蛋白的vgl 1+和编码多聚腺苷酸结合蛋白的pab 1+，导致对阿霉素的敏感性高于野生型细胞。vgl 1+和pab 1+基因的破坏并没有赋予对其他抗癌药物（例如顺铂、5-氟尿嘧啶和紫杉醇）的敏感性。我们还表明，阿霉素治疗促进应激颗粒形成时，结合热休克。值得注意的是，多柔比星处理没有诱导eIF 2 α的过度磷酸化，表明多柔比星参与了不依赖于eIF 2 α磷酸化的应激颗粒组装。我们的研究结果表明，有用的裂变酵母阐明阿霉素毒性的分子靶点，并提出了一种新的耐药机制，涉及应力颗粒组装。
Doxorubicin is an anthracycline antibiotic widely used for chemotherapy. Although doxorubicin is effective in the treatment of several cancers, including solid tumors and leukemias, the basis of its mechanism of action is not completely understood. Here, we describe the effects of doxorubicin and its relationship with stress granules formation in the fission yeast, Schizosaccharomyces pombe. We show that disruption of genes encoding the components of stress granules, including vgl1+, which encodes a multi-KH type RNA-binding protein, and pab1+, which encodes a poly(A)-binding protein, resulted in greater sensitivity to doxorubicin than seen in wild-type cells. Disruption of the vgl1+and pab1+genes did not confer sensitivity to other anti-cancer drugs such as cisplatin, 5-fluorouracil, and paclitaxel. We also showed that doxorubicin treatment promoted stress granule formation when combined with heat shock. Notably, doxorubicin treatment did not induce hyperphosphorylation of eIF2α, suggesting that doxorubicin is involved in stress granule assembly independent of eIF2α phosphorylation. Our results demonstrate the usefulness of fission yeast for elucidating the molecular targets of doxorubicin toxicity and suggest a novel drug-resistance mechanism involving stress granule assembly.