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PAK1-dependent MAPK pathway activation is required for colorectal cancer cell proliferation

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Tumor Biology

Abstract

P21-activated protein kinase1 (PAK1), a main downstream effector of small Rho GTPases, Rac1, and Cdc42, plays an important role in the regulation of cell morphogenesis, motility, mitosis, and angiogenesis. Despite its importance, the molecular mechanisms of PAK1 that contributed to colorectal carcinogenesis remain unclear. Our immunohistochemistry showed that PAK1 expression was increased with colorectal cancer (CRC) progression through the adenoma to carcinoma sequence. Furthermore, our results suggested a relationship between PAK1 nuclear localization and the Dukes staging. In the present study, we showed that PAK1 knockdown decreased proliferation and delayed the G1/S cell-cycle transition, and increased apoptosis in vivo and in vitro. In addition, PAK1 knock-down downregulated c-Jun amino terminal kinases (JNK) activity and the levels of cyclinD1, CDK4/6. Inhibition of the JNK activity by chemical inhibitor (SP600125) significantly reduced the effects of PAK1 on CRC proliferation via accumulation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN). In conclusion, our results demonstrate that knockdown of PAK1 could enhance the chemosensitivity of CRCs to 5-fluorouracil through G1 arrest. The mechanism by which PAK1 induced cancer growth might involve activation of JNK as well as downregulation of PTEN. Targeting PAK1 may represent a novel treatment strategy for developing novel chemotherapeutic agents.

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Acknowledgments

Grant support: The Nature Science Foundation of China grant 30830048 and 973 Program of the Ministry of Science and Technology of China (2010CB912203) to Hongquan Zhang. We thank Dr. Feici Diao for critical reading of the manuscript, Dr. Hua Tian for providing the pcDNA3.1(+)-PTEN and vector plasmids, and Dr. Yan Sun for helpful advice with the siRNA, cell cycle, and apoptosis experiments.

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Authors and Affiliations

  1. Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People’s Republic of China

    Haitao Qing, Wei Gong, Yufang Che, Xinying Wang, Liang Peng, Yan Liang, Qiliang Deng & Bo Jiang

  2. Department of Gastroenterology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, 510630, People’s Republic of China

    Weifei Wang

  3. Laboratory of Molecular Cell Biology and Tumor Biology, Key Laboratory of Carcinogenesis and Translational Research, The Ministry of Education, Department of Histology and Embryology, Peking University Health Science Center, Beijing, 100191, People’s Republic of China

    Hongquan Zhang

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  1. Haitao Qing
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  2. Wei Gong
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Correspondence to Bo Jiang.

Additional information

Haitao Qing and Wei Gong contributed equally to this work.

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Supplementary Fig. 1

Nuclear localization of PAK1. (a) and (b) are representatives which have strong PAK1 immunoactivity in the nucleus as well as in the cytoplasm. a, b: ×400 (JPEG 26 kb)

High resolution image (TIFF 1048 kb)

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Qing, H., Gong, W., Che, Y. et al. PAK1-dependent MAPK pathway activation is required for colorectal cancer cell proliferation. Tumor Biol. 33, 985–994 (2012). https://doi.org/10.1007/s13277-012-0327-1

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