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CIP2A 沉默通过激活 PP2A 和自噬来减轻 MCF7/ADR 细胞中的多柔比星耐药性。

CIP2A silencing alleviates doxorubicin resistance in MCF7/ADR cells through activating PP2A and autophagy.

机构信息

Department of Radiotherapy, Cangzhou Central Hospital, No.16 Xinhua West Rd, Cangzhou city, Hebei Province, 061000, China.

Thyroid and Breast Department, Cangzhou Central Hospital, No.16 Xinhua West Rd, Cangzhou city, Hebei Province, 061000, China.

出版信息

Clin Transl Oncol. 2021 Aug;23(8):1542-1548. doi: 10.1007/s12094-021-02616-7. Epub 2021 May 4.

DOI:10.1007/s12094-021-02616-7
PMID:33948919
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8238779/
Abstract

BACKGROUND

Cancerous inhibitor of protein phosphatase 2A (CIP2A) plays a critical role in the pathogenesis of various types of cancer. Here, we investigated whether manipulating CIP2A abundance could enhance the treatment effects of doxorubicin in MCF-7/ADR cells.

METHODS

CIP2A silencing was achieved by specific siRNAs. Proliferation of breast cancer cell line MCF-7/ADR under effective doxorubicin concentrations after CIP2A silencing was examined by MTT assay. Wound healing assay was performed to quantify cell migration and caspase-3/-7 activities were measured for assessing the extent of apoptosis.

RESULTS

First, our data confirmed that MCF-7/ADR cell proliferation was suppressed by doxorubicin in a dose-dependent manner. Additionally, knocking down of CIP2A could further decrease MCF-7 cell proliferation and migration, even in the presence of doxorubicin. Mechanistically, we have found that CIP2A silencing promoted cell apoptosis relative to doxorubicin alone or vehicle control groups. Lastly, phosphatase2A (PP2A) activity was potentiated and the autophagy markers, LC3B and Beclin1, were upregulated after knocking down CIP2A.

CONCLUSION

Our findings support the potential benefits of using CIP2A inhibitor as a therapeutic agent to treat doxorubicin-resistant breast cancer.

摘要

背景

癌性蛋白磷酸酶 2A 抑制剂（CIP2A）在多种类型癌症的发病机制中起着关键作用。在这里，我们研究了操纵 CIP2A 丰度是否可以增强多柔比星在 MCF-7/ADR 细胞中的治疗效果。

方法

通过特异性 siRNA 实现 CIP2A 沉默。沉默 CIP2A 后，通过 MTT 测定法检测有效多柔比星浓度下乳腺癌细胞系 MCF-7/ADR 的增殖。进行划痕愈合试验以量化细胞迁移，并且测量 caspase-3/-7 活性以评估细胞凋亡的程度。

结果

首先，我们的数据证实 MCF-7/ADR 细胞增殖被多柔比星以剂量依赖性方式抑制。此外，敲低 CIP2A 甚至在存在多柔比星的情况下，也可以进一步降低 MCF-7 细胞的增殖和迁移。从机制上讲，我们发现与单独使用多柔比星或载体对照组相比，沉默 CIP2A 可促进细胞凋亡。最后，敲低 CIP2A 后，磷酸酶 2A（PP2A）活性增强，自噬标记物 LC3B 和 Beclin1 上调。

结论

我们的研究结果支持使用 CIP2A 抑制剂作为治疗多柔比星耐药性乳腺癌的治疗剂的潜在益处。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41a4/8238779/9ef6ca475d31/12094_2021_2616_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41a4/8238779/8cde41a8ec76/12094_2021_2616_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41a4/8238779/aedb6e90c948/12094_2021_2616_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41a4/8238779/01ba78e78894/12094_2021_2616_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41a4/8238779/131ab6a07357/12094_2021_2616_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41a4/8238779/add6593ab418/12094_2021_2616_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41a4/8238779/9ef6ca475d31/12094_2021_2616_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41a4/8238779/8cde41a8ec76/12094_2021_2616_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41a4/8238779/aedb6e90c948/12094_2021_2616_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41a4/8238779/01ba78e78894/12094_2021_2616_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41a4/8238779/131ab6a07357/12094_2021_2616_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41a4/8238779/add6593ab418/12094_2021_2616_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41a4/8238779/9ef6ca475d31/12094_2021_2616_Fig6_HTML.jpg

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