Doxorubicin blocks proliferation of cancer cells through proteolytic activation of CREB3L1.
Doxorubicin blocks proliferation of cancer cells through proteolytic activation of CREB3L1.
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作者：
Denard B;Lee C;Ye J
多柔比星被广泛用于各种类型癌症的化疗，但其抑制癌细胞增殖的机制仍不清楚。在这里，我们报告说，阿霉素刺激从头合成的神经酰胺，这反过来又激活CREB 3L 1，一个转录因子作为膜结合的前体合成。多柔比星通过位点-1蛋白酶和位点-2蛋白酶刺激CREB 3L 1的蛋白水解切割，允许CREB 3L 1的NH 2-末端结构域进入细胞核，在那里它激活编码细胞周期抑制剂（包括p21）的基因的转录。人肝癌Huh 7细胞和永生化人成纤维细胞SV 589细胞中CREB 3L 1 mRNA的敲低赋予了对阿霉素的耐药性增加，而人乳腺癌MCF-7细胞中CREB 3L 1的过表达显著增强了这些细胞对阿霉素的敏感性。这些结果表明，CREB 3L 1表达的测量可能是鉴定对阿霉素敏感的癌细胞的有用生物标志物。DOI：http://dx.doi.org/10.7554/eLife.00090.001癌症是一个广义的术语，描述了200多种由细胞以失控的方式增殖引起的疾病。细胞复制和分裂通常受到非常严格的调节，并且随着细胞变老，受损或突变，它们要么被修复，要么经历程序性细胞死亡（凋亡）。然而，如果有缺陷的细胞继续复制，所产生的异常细胞簇可能会癌变。有这么多不同类型的癌症，没有“灵丹妙药”可以治愈所有癌症。许多癌症疗法都是靶向的，依赖于通过干扰参与某些肿瘤生长和进展的特定分子来阻断癌症扩散的药物。然而，在许多形式的癌症中，病变细胞比正常细胞复制得更快的事实使得在靶向治疗不可用时使用非特异性药物（如阿霉素）来治疗肿瘤成为可能。多柔比星可通过抑制拓扑异构酶II的活性而在多种不同癌症中诱导DNA断裂，但尚未建立这种酶的抑制与细胞增殖的阻断之间的一致关系。由于对阿霉素抑制细胞增殖的机制缺乏了解，因此很难确定哪些癌症患者最有可能从阿霉素治疗中获益。Denard等人现在已经表明，阿霉素通过切割称为CREB 3L 1的转录因子来阻断细胞复制。这项最新的工作建立在以前的工作基础上，他们表明这种转录因子的切割可以抑制感染丙型肝炎病毒的细胞的复制。自2000年以来已知CREB 3L 1是一种膜蛋白，其一端在内质网腔内，另一端（以NH 2基团终止）在细胞的胞质溶胶中。当CREB 3L 1被切割时，NH 2末端结构域进入细胞核，在那里它驱动抑制细胞周期的基因的转录。Denard等人清楚地表明，多柔比星通过刺激神经酰胺分子的产生来触发CREB 3L 1的裂解。因此，随着进一步的研究，有可能使用CREB 3L 1作为生物标志物来识别适合多柔比星治疗的肿瘤。DOI：http://dx.doi.org/10.7554/eLife.00090.002网站
Doxorubicin is used extensively for chemotherapy of diverse types of cancer, yet the mechanism through which it inhibits proliferation of cancer cells remains unclear. Here we report that doxorubicin stimulates de novo synthesis of ceramide, which in turn activates CREB3L1, a transcription factor synthesized as a membrane-bound precursor. Doxorubicin stimulates proteolytic cleavage of CREB3L1 by Site-1 Protease and Site-2 Protease, allowing the NH2-terminal domain of CREB3L1 to enter the nucleus where it activates transcription of genes encoding inhibitors of the cell cycle, including p21. Knockdown of CREB3L1 mRNA in human hepatoma Huh7 cells and immortalized human fibroblast SV589 cells conferred increased resistance to doxorubicin, whereas overexpression of CREB3L1 in human breast cancer MCF-7 cells markedly enhanced the sensitivity of these cells to doxorubicin. These results suggest that measurement of CREB3L1 expression may be a useful biomarker in identifying cancer cells sensitive to doxorubicin. DOI: http://dx.doi.org/10.7554/eLife.00090.001 Cancer is a broad term to describe over 200 diseases that are caused by cells proliferating in an out-of-control manner. Cell replication and division are normally very tightly regulated, and as cells become old, damaged or mutated, they are either repaired or undergo programmed cell death (apoptosis). However, if defective cells continue to replicate, the resulting clusters of abnormal cells can become cancerous. With so many different types of cancer, there is no ‘magic bullet’ to cure all of them. Many cancer therapies are targeted, relying on drugs that block the spread of cancer by interfering with specific molecules involved in the growth and progression of certain tumors. However, the fact that diseased cells replicate faster than normal cells in many forms of cancer makes it possible to use non-specific drugs, such as doxorubicin, to treat tumors when targeted therapies are not available. Doxorubicin can induce DNA breaks in a variety of different cancers by inhibiting the activity of topoisomerase II but a consistent relationship between the inhibition of this enzyme and the blocking of cell proliferation has not been established. This lack of understanding of the mechanism through which doxorubicin inhibits cell proliferation makes it difficult to identify cancer patients who are most likely to benefit from doxorubicin treatment. Denard et al. have now shown that doxorubicin blocks cell replication by cleaving a transcription factor called CREB3L1. This latest work builds on previous work in which they showed that cleavage of this transcription factor can inhibit the replication of cells infected with hepatitis C virus. It has been known since 2000 that CREB3L1 is a membrane protein with one end inside the lumen of the endoplasmic reticulum, and the other end (which is terminated with an NH2 group) in the cytosol of the cell. When CREB3L1 is cleaved, the NH2-terminal domain travels into the nucleus of the cell, where it drives the transcription of genes that suppress the cell cycle. Denard et al. clearly show that doxorubicin triggers the cleavage of CREB3L1 by stimulating the production of ceramide molecules. Thus, It might be possible, with further research, to use CREB3L1 as a biomarker to identify tumors that are suitable for treatment by doxorubicin. DOI: http://dx.doi.org/10.7554/eLife.00090.002