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CDK1 蛋白异常的上游通路调控与卵巢癌细胞的增殖和凋亡有关。

The aberrant upstream pathway regulations of CDK1 protein were implicated in the proliferation and apoptosis of ovarian cancer cells.

机构信息

Department of Gynecology, First Affiliated Hospital, Zhengzhou University, NO.1 Jianshe Road, Zhengzhou, 450052, Henan, People's Republic of China.

出版信息

J Ovarian Res. 2017 Sep 12;10(1):60. doi: 10.1186/s13048-017-0356-x.

DOI:10.1186/s13048-017-0356-x
PMID:28899430
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5596843/
Abstract

BACKGROUND

Upregulation of Cyclin dependent kinase 1 (CDK1) protein is closely related with the prognosis of several malignant tumors. Chk1-CDC25C-CDK1 signaling and P53-P21WAF1-CDK1 signaling pathways are closely related with the cell cycle G2/M phase regulation. The present study aimed to analyze the relationship between CDK1 and the proliferation and apoptosis of ovarian cancer cells, investigate its molecular mechanism preliminarily.

METHODS

The specific short-hair RNA (shRNA) plasmids and negative control plasmid of CDK1, checkpoint kinase 1 (CHK1) and p53 genes were transfected into ovarian cancer SK-OV-3 and OVCAR-3 cells respectively. The expressions of CDK1, CHK1 and p53 mRNA and CDK1, Chk1 and P53 protein were detected by sqRT-PCR and Western blot, levels of phospho-CDK1(Thr14/Tyr15), CyclinB1, phospho-Chk1(ser345), cell division cycle 25C (CDC25C), phospho-CDC25C(ser216), P21WAF1, phospho-P53(ser15), proliferating cell nuclear antigen (PCNA), Ki-67, Bcl-2, Bax, Caspase8, Cleaved-caspase3 and Cytochrome C were examined by Western blot. The cell proliferation was measured by MTT and Trypan blue exclusion assay respectively, the cell cycle phase distribution and cell apoptosis rate were detected by flow cytometry (FCM) assay.

RESULTS

As results of CDK1 inhibition by shRNA, the cell proliferation was repressed, the cell numbers of G2/M phase and cell apoptosis rate were increased in both SK-OV-3 and OVCAR-3 cells. After knockdown of CDK1, expressions of PCNA, Ki-67 and Bcl-2 protein were downregulated, expressions of Bax, Caspase8, Cleaved-caspase3 and Cytochrome C were upregulated. While knockdown the CHK1 and p53 by shRNA respectively, the similar effects were observed on the cell proliferation, cell cycle phase distribution and apoptosis in both SK-OV-3 and OVCAR-3 cells, as well as the expressions of the proliferation and apoptosis related proteins mentioned above. Moreover, the levels of p-CDK1(Thr14/Tyr15) were increased after either CHK1 inhibition or p53 inhibition.

CONCLUSIONS

Abnormal activation of CDK1 was implicated in the proliferation and apoptosis regulation of ovarian cancer cells, which might be due to the aberrant regulations of the upstream Chk1-CDC25C and P53-P21WAF1 signaling pathway.

摘要

背景

细胞周期蛋白依赖性激酶 1（CDK1）蛋白的上调与几种恶性肿瘤的预后密切相关。Chk1-CDC25C-CDK1 信号通路和 P53-P21WAF1-CDK1 信号通路与细胞周期 G2/M 期调节密切相关。本研究旨在分析 CDK1 与卵巢癌细胞增殖和凋亡的关系，初步探讨其分子机制。

方法

分别将 CDK1、检查点激酶 1（CHK1）和 p53 基因的特异性短发夹 RNA（shRNA）质粒和阴性对照质粒转染到卵巢癌细胞 SK-OV-3 和 OVCAR-3 中。sqRT-PCR 和 Western blot 检测 CDK1、CHK1 和 p53mRNA 及 CDK1、Chk1 和 P53 蛋白的表达水平，Western blot 检测磷酸化 CDK1（Thr14/Tyr15）、细胞周期蛋白 B1、磷酸化 Chk1（ser345）、细胞分裂周期 25C（CDC25C）、磷酸化 CDC25C（ser216）、P21WAF1、磷酸化 P53（ser15）、增殖细胞核抗原（PCNA）、Ki-67、Bcl-2、Bax、Caspase8、Cleaved-caspase3 和细胞色素 C 的水平。MTT 和台盼蓝排除试验分别检测细胞增殖，流式细胞术（FCM）检测细胞周期分布和细胞凋亡率。

结果

shRNA 抑制 CDK1 后，SK-OV-3 和 OVCAR-3 细胞的增殖受到抑制，G2/M 期细胞数和细胞凋亡率增加。CDK1 敲低后，PCNA、Ki-67 和 Bcl-2 蛋白表达下调，Bax、Caspase8、Cleaved-caspase3 和细胞色素 C 蛋白表达上调。shRNA 分别敲低 CHK1 和 p53 后，SK-OV-3 和 OVCAR-3 细胞的增殖、细胞周期分布和凋亡以及上述增殖和凋亡相关蛋白的表达均出现类似变化。此外，CHK1 抑制或 p53 抑制后，p-CDK1（Thr14/Tyr15）水平升高。

结论

CDK1 的异常激活参与了卵巢癌细胞的增殖和凋亡调节，这可能是由于上游 Chk1-CDC25C 和 P53-P21WAF1 信号通路的异常调节所致。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0bc3/5596843/51e3d4ef831f/13048_2017_356_Fig10_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0bc3/5596843/3c72e9f45134/13048_2017_356_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0bc3/5596843/51e3d4ef831f/13048_2017_356_Fig10_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0bc3/5596843/74bec239ccbe/13048_2017_356_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0bc3/5596843/f65201ad54cb/13048_2017_356_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0bc3/5596843/6c3aabd1e715/13048_2017_356_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0bc3/5596843/8ff9e3a03b16/13048_2017_356_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0bc3/5596843/e3abddb20ad3/13048_2017_356_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0bc3/5596843/4cb65369b767/13048_2017_356_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0bc3/5596843/e01a3c020462/13048_2017_356_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0bc3/5596843/16cab2abc8b8/13048_2017_356_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0bc3/5596843/3c72e9f45134/13048_2017_356_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0bc3/5596843/51e3d4ef831f/13048_2017_356_Fig10_HTML.jpg

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