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Down-regulation of phospho-non-receptor Src tyrosine kinases contributes to growth inhibition of cervical cancer cells

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Abstract

Non-receptor Src tyrosine kinases (nrTKs) are overexpressed in a variety of human tumors, including cancer of the colon, breast, and pancreas, and their inhibitors are under intensive investigations as novel anti-tumor agents. However, these studies are not clear in the case of cervical cancer. Therefore, we studied the role of nrTKs and their inhibitors in the cervical cancer. The expression level of phospho-SrcY416 (pSrcY416) in several cervical cancer cell lines, normal cervical tissues, and cervical cancer tissues have been examined, and it has also been done whether PP2, an inhibitor of Src kinase, can inhibit the growth of cervical cells in vitro and in vivo. Immunohistochemical and confocal microscope studies suggested that pSrcY416 is overexpressed in HeLa and SiHa cells, as well as in the clinical cervical cancer tissues, compared to the normal cervical tissues. Down-regulation of pSrcY416 inhibited the cell proliferation by increasing the HeLa or SiHa cell population in the G0-G1 phase or S phase, respectively. Down-regulation of pSrcY416 led to up-regulation of p21Cip1 and p27Kip1 in both HeLa and SiHa cells and decreased the expression of cyclin A1, cyclin E, and cyclin-dependent kinase-2,-6 (CDK-2,-6) in HeLa cells and of cyclin B and CDK-2 in SiHa cells. Nude mice xenograft data showed that PP2 inhibited subcutaneous tumor growth significantly (P < 0.05, compared with the control). Down-regulation of pSrcY416 contributes to cell growth inhibition in cervical cancer cells. nrTKs could therefore be a novel therapeutic targets for the treatment of cervical cancer.

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Abbreviations

nrTKs:

Non-receptor tyrosine kinases

pSrcY416 :

Phospho-SrcY416

Src:

Sarcoma

HPV:

Human papillomavirus

CDK:

Cyclin-dependent kinase

CDKIs:

Cyclin-dependent kinase inhibitors

siRNA:

Small interfering RNA

PP2:

4-Amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazolo (3, 4-d) pyrimidine

cisplatin:

Cis-diamminedichloroplatinum

MTT:

3-(4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide

OD:

Optical density

FIGO:

International federation of gynecologists and obstetricians

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Acknowledgments

This study was financially supported by grants from the National Natural Sciences Foundation of China (30672422) and Major State Basic Research Development Programs (2009CB521800; 2010CB529400). The authors wish to acknowledge Ms. Peilan Yu and Ms. Xiaobei Zeng for assistance with the animal experiments and Ms. Xingcui Wang for the flow cytometry and Professor Norm Davison and Ms. Aihong Song for text editing.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Cancer Institute, Capital Medical University, No. 10 Xitoutiao, You An Men, 100069, Beijing, China

    Lu Kong, Zhihong Deng, Yamei Wang & Yuxiang Zhang

  2. Fu Xing Hospital, Capital Medical University, Beijing, China

    Yanzhong Zhao

  3. Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, 740 HWCRC, 4100 John R, Detroit, MI, 48202, USA

    Fazlul H. Sarkar

Authors
  1. Lu Kong
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  2. Zhihong Deng
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  3. Yanzhong Zhao
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  4. Yamei Wang
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  5. Fazlul H. Sarkar
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  6. Yuxiang Zhang
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Correspondence to Yuxiang Zhang.

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Lu Kong and Zhihong Deng are co-first authorship.

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Kong, L., Deng, Z., Zhao, Y. et al. Down-regulation of phospho-non-receptor Src tyrosine kinases contributes to growth inhibition of cervical cancer cells. Med Oncol 28, 1495–1506 (2011). https://doi.org/10.1007/s12032-010-9583-3

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  • DOI: https://doi.org/10.1007/s12032-010-9583-3

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