High expression of PSF1 promotes drug resistance and cell cycle transit in leukemia cells
High expression of PSF1 promotes drug resistance and cell cycle transit in leukemia cells
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DOI：
10.1111/cas.14452
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发表时间：
2020-06-01
期刊：
影响因子：
5.7
通讯作者：
Takakura, Nobuyuki
中科院分区：
文献类型：
--
作者：
Hsieh, Han-Yun;Jia, Weizhen;Takakura, Nobuyuki
癌细胞从化疗中逃逸是癌症患者管理中的一个问题。化疗耐药的研究主要集中在癌细胞的异质性、多基因突变和恶性癌细胞的静止性。然而，一些研究表明，癌细胞和血管细胞之间的相互作用促进了对化疗的抵抗。在此，我们使用细胞系THP-1或MEG-1建立小鼠白血病模型。这些细胞分别来自急性和慢性髓性白血病，并且高度表达DNA复制因子PSF 1，GINS复合物的一个成员。我们发现，在抗癌药物给药后，骨髓中存活的GFP阳性白血病细胞位于血管附近，正如先前在皮下实体瘤移植模型中报道的那样。在体外用抗癌药物处理THP-1和MEG-1细胞显示，那些最强烈表达PSF 1的细胞是最耐药的，这表明PSF 1不仅诱导细胞周期进展，而且促进细胞存活。事实上，当PSF 1表达被shRNA抑制时，两种细胞系的生长速率降低，细胞死亡增加。此外，在骨髓移植模型中，白血病细胞中的PSF 1敲低导致其位置发生变化，与血管有一定距离。这些发现可能反映了白血病细胞逃避化疗的机制，并表明PSF 1可能是一个可能的治疗靶点，以提高化疗的效果。
Escape of cancer cells from chemotherapy is a problem in the management of cancer patients. Research on chemotherapy resistance has mainly focused on the heterogeneity of cancer cells, multiple gene mutations, and quiescence of malignant cancer cells. However, some studies have indicated that interactions between cancer cells and vascular cells promote resistance to chemotherapy. Here, we established mouse leukemia models using the cell lines THP-1 or MEG-1. These were derived from acute and chronic myeloid leukemias, respectively, and highly expressed DNA replication factor PSF1, a member of the GINS complex. We found that, after anti-cancer drug administration, surviving GFP-positive leukemia cells in the bone marrow were located adjacent to blood vessels, as previously reported in a subcutaneous solid tumor transplantation model. Treating THP-1 and MEG-1 cells with anti-cancer drugs in vitro revealed that those most strongly expressing PSF1 were most chemoresistant, suggesting that PSF1 induces not only cell cycle progression but also facilitates cell survival. Indeed, when PSF1 expression was suppressed by shRNA, the growth rate was reduced and cell death was enhanced in both cell lines. Furthermore, PSF1 knockdown in leukemia cells led to a change in their location at a distance from the blood vessels in a bone marrow transplantation model. These findings potentially reflect a mechanism of escape of leukemic cells from chemotherapy and suggest that PSF1 may be a possible therapeutic target to enhance the effect of chemotherapy.