Medical Scientist Training Program, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin.
Department of Medicine, Division of Hematology/Oncology, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin.
Mol Cancer Res. 2018 Mar;16(3):517-527. doi: 10.1158/1541-7786.MCR-17-0197. Epub 2018 Jan 12.
Centrosome amplification (CA) is common in cancer and can arise by centriole overduplication or by cell doubling events, including the failure of cell division and cell-cell fusion. To assess the relative contributions of these two mechanisms, the number of centrosomes with mature/mother centrioles was examined by immunofluorescence in a tissue microarray of human melanomas and benign nevi ( = 79 and 17, respectively). The centrosomal protein 170 (CEP170) was used to identify centrosomes with mature centrioles; this is expected to be present in most centrosomes with cell doubling, but on fewer centrosomes with overduplication. Using this method, it was determined that the majority of CA in melanoma can be attributed to centriole overduplication rather than cell doubling events. As Polo-like kinase 4 (PLK4) is the master regulator of centriole duplication, the hypothesis that PLK4 overexpression contributes to centriole overduplication was evaluated. PLK4 is significantly overexpressed in melanoma compared with benign nevi and in a panel of human melanoma cell lines (A375, Hs294T, G361, WM35, WM115, 451Lu, and SK-MEL-28) compared with normal human melanocytes. Interestingly, although PLK4 expression did not correlate with CA in most cases, treatment of melanoma cells with a selective small-molecule PLK4 inhibitor (centrinone B) significantly decreased cell proliferation. The antiproliferative effects of centrinone B were also accompanied by induction of apoptosis. This study demonstrates that centriole overduplication is the predominant mechanism leading to centrosome amplification in melanoma and that PLK4 should be further evaluated as a potential therapeutic target for melanoma treatment. .
中心体扩增（CA）在癌症中很常见，其发生机制可以是中心体的过度复制，也可以是细胞倍增事件，包括细胞分裂失败和细胞融合。为了评估这两种机制的相对贡献，通过免疫荧光法在人黑色素瘤和良性痣的组织微阵列中检查了具有成熟/母中心体的中心体数量（分别为 79 个和 17 个）。中心体蛋白 170（CEP170）用于识别具有成熟中心体的中心体；这有望存在于大多数具有细胞倍增的中心体中，但在具有过度复制的中心体中则较少。使用这种方法，确定黑色素瘤中的大多数 CA 可归因于中心体的过度复制，而不是细胞倍增事件。由于 Polo 样激酶 4（PLK4）是中心体复制的主要调节因子，因此评估了 PLK4 过表达有助于中心体过度复制的假设。与良性痣相比，PLK4 在黑色素瘤中显著过表达，并且与一组人黑色素瘤细胞系（A375、Hs294T、G361、WM35、WM115、451Lu 和 SK-MEL-28）相比，正常黑素细胞中也过表达。有趣的是，尽管在大多数情况下 PLK4 表达与 CA 无关，但用选择性小分子 PLK4 抑制剂（centrinone B）处理黑色素瘤细胞可显著降低细胞增殖。centrinone B 的抗增殖作用还伴随着细胞凋亡的诱导。这项研究表明，中心体的过度复制是导致黑色素瘤中心体扩增的主要机制，并且应该进一步评估 PLK4 作为治疗黑色素瘤的潜在治疗靶点。
