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PAK1 silencing is synthetic lethal with CDK4/6 inhibition in gastric cancer cells via regulating PDK1 expression

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Abstract

Gastric cancer (GC) is one of the most common malignancies worldwide. The prognosis of GC is unsatisfied owning to widespread metastasis. P21-activated kinase 1 (PAK1), a member of serine/threonine kinases, is associated with the progression of multiple types of human cancers. Here, we demonstrated that CDK4/6 inhibitor reduced GC cell viability and decreased PAK1 expression. Consistently, PAK1 ablation increased GC cell sensitivity exposed to CDK4/6 inhibitor and promoted DNA damage. We also revealed PAK1 depletion notably affected PDK1-AKT pathway, and PDK1 overexpression totally abrogated the effect of PAK1 deletion on DNA damage in GC cells. Additionally, PDK1 overexpression also rescued the increased GC cell sensitivity towards CDK4/6 inhibitor and the cell cycle arrest caused by PAK1 depletion. Our findings, therefore, suggested that PAK1 silencing increased sensitivity to CDK4/6 inhibition in gastric cancer cells via PDK1–AKT pathway. We, therefore, thought PAK1 as a promising therapeutic target for the treatment of CDK4/6 inhibitor-resistant gastric cancer.

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Authors and Affiliations

  1. Department of Gastric, The Affiliated Huaian No.1 People’s Hospital of Nanjing Medical University, Huai’an, 223300, Jiangsu, China

    Yan Qian, Xu Wu, Haixiao Wang, Guowei Hou & Xiao Han

  2. Department of Gastroenterlogy, The Affiliated Huaian No.1 People’s Hospital of Nanjing Medical University, No. 1 Huanghe West Road, Huaiyin, Huai’an, 223300, Jiangsu, China

    Wei Song

Authors
  1. Yan Qian
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  2. Xu Wu
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  3. Haixiao Wang
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  4. Guowei Hou
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  5. Xiao Han
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  6. Wei Song
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Contributions

WS and YQ conceived and designed the experiments, XW and HXW analyzed and interpreted the results of the experiments, and GWH and XH performed the experiments.

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Correspondence to Wei Song.

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Qian, Y., Wu, X., Wang, H. et al. PAK1 silencing is synthetic lethal with CDK4/6 inhibition in gastric cancer cells via regulating PDK1 expression. Human Cell 33, 377–385 (2020). https://doi.org/10.1007/s13577-019-00317-6

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  • DOI: https://doi.org/10.1007/s13577-019-00317-6

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