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c-Src 对人卵巢癌细胞缺氧耐药性对紫杉醇的影响及 FV-429 的逆转。

Influence of c-Src on hypoxic resistance to paclitaxel in human ovarian cancer cells and reversal of FV-429.

机构信息

State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People's Republic of China.

Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People's Republic of China.

出版信息

Cell Death Dis. 2018 Jan 11;8(1):e3178. doi: 10.1038/cddis.2017.367.

DOI:10.1038/cddis.2017.367
PMID:29324735
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5827169/
Abstract

SRC family kinase was documented to have vital roles in adjusting cancer cell malignant behaviors. To date, the role of c-Src, a member of SRC family kinase, in resistance to paclitaxel in human ovarian cancer cells under hypoxia has not been investigated. In the present study, we discovered that hypoxic environment suppressed paclitaxel-induced G2/M phase arrest and blockade of c-Src improved ovarian cancer cells' sensitivity to paclitaxel. FV-429, a derivative of natural flavonoid wogonin, could suppress gene expression and activation of c-Src, followed by deteriorated Stat3 nuclear translocation and its binding to HIF-1α, resulting in paclitaxel resistance reversal through G2/M arrest potentiation. Our study demonstrated that c-Src contributed to hypoxic microenvironment-rendered paclitaxel resistance in human epithelial ovarian cancer cells by G2/M phase arrest deterioration, and through c-Src suppression, FV-429 was capable of reversing the resistance by blocking c-Src/Stat3/HIF-1α pathway.

摘要

Src 家族激酶被证明在调节癌细胞恶性行为方面具有重要作用。迄今为止，Src 家族激酶成员 c-Src 在缺氧条件下对人卵巢癌细胞紫杉醇耐药性中的作用尚未被研究。在本研究中，我们发现低氧环境抑制了紫杉醇诱导的 G2/M 期阻滞，而抑制 c-Src 可提高卵巢癌细胞对紫杉醇的敏感性。FV-429 是天然黄酮类化合物白杨素的衍生物，可抑制 c-Src 的基因表达和激活，随后 Stat3 核易位及其与 HIF-1α 的结合恶化，从而通过增强 G2/M 期阻滞来逆转紫杉醇耐药性。我们的研究表明，c-Src 通过 G2/M 期阻滞恶化导致人上皮性卵巢癌细胞对低氧微环境中紫杉醇的耐药性，并且通过抑制 c-Src，FV-429 能够通过阻断 c-Src/Stat3/HIF-1α 通路来逆转耐药性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e802/5827169/c0625b5e96c2/cddis2017367f7.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e802/5827169/e56aae934940/cddis2017367f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e802/5827169/2264e9d02ce1/cddis2017367f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e802/5827169/c8863b6f3349/cddis2017367f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e802/5827169/c0625b5e96c2/cddis2017367f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e802/5827169/fd634f8d82a5/cddis2017367f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e802/5827169/322ebc720e7f/cddis2017367f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e802/5827169/3dcb70b159b5/cddis2017367f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e802/5827169/e56aae934940/cddis2017367f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e802/5827169/2264e9d02ce1/cddis2017367f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e802/5827169/c8863b6f3349/cddis2017367f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e802/5827169/c0625b5e96c2/cddis2017367f7.jpg

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