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The P21-activated kinase expression pattern is different in non-small cell lung cancer and affects lung cancer cell sensitivity to epidermal growth factor receptor tyrosine kinase inhibitors

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Abstract

Exploring methods for increasing epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) sensitivity has become a major focus in non-small cell lung cancer (NSCLC). Major downstream effectors of the Rho family small guanosine triphosphatases, P21-activated kinases (PAKs) activate the main signaling pathways downstream of EGFR and thus promote tumor cell proliferation. In this study, we explored the expression pattern of phosphorylated PAKs in NSCLC and their potential value as drug targets for treating cancer. The expression and prognostic significance of phosphorylated group I and II PAKs were evaluated in 182 patients with NSCLC. Immunohistochemical analysis revealed low group I PAK expression in normal lung tissues and increased expressed in the cytoplasm, particularly in lung squamous cell carcinoma. Abnormal group I PAK expression was associated with lymph node metastases and high tumor-node-metastases (TNM) stage in NSCLC patients and correlated with poor prognosis. We used group I PAK inhibitor (IPA3) to specifically decrease group I PAK activity in human lung cancer cell lines. Decreased group I PAK activity inhibited cell proliferation and combined IPA3 and EGFR-TKI (gefitinib) treatment inhibited cell proliferation in an obvious manner. Together, our results revealed the PAK expression pattern in NSCLC, and a role for group I PAK in cell proliferation, which provides evidence that decreased PAK activity may have a potential application as a molecular targeted therapy in advanced NSCLC.

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Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (No. 30900562 to Yang Liu and No. 81302022 to Qian-Ze Dong), the Foundation of Liaoning Educational Committee (No. L2015583 to Yang Liu), and the Foundation of Liaoning Science and Technology Committee (No. 65233037 to Si Wang). All the authors of this manuscript have no actual or potential conflict related to this work.

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Authors and Affiliations

  1. Department of Pathology, The First Affiliated Hospital and College of Basic Medical Sciences of China Medical University, Shenyang, 110001, People’s Republic of China

    Yang Liu, Qian-Ze Dong, Gui-Yang Jiang, Yong Han, Liang Wang & En-Hua Wang

  2. Department of Medical Microbiology and Parasitology, College of Basic Medical Sciences of China Medical University, Shenyang, 110001, People’s Republic of China

    Si Wang

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  1. Yang Liu
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  2. Si Wang
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Correspondence to Yang Liu.

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Liu, Y., Wang, S., Dong, QZ. et al. The P21-activated kinase expression pattern is different in non-small cell lung cancer and affects lung cancer cell sensitivity to epidermal growth factor receptor tyrosine kinase inhibitors. Med Oncol 33, 22 (2016). https://doi.org/10.1007/s12032-016-0735-y

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  • DOI: https://doi.org/10.1007/s12032-016-0735-y

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