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JNK1/2 represses Lkb1-deficiency-induced lung squamous cell carcinoma progression

Author

Listed:
  • Jian Liu

    (National Institute of Environmental Health Sciences (NIEHS))

  • Tianyuan Wang

    (National Institute of Environmental Health Sciences (NIEHS))

  • Chad J. Creighton

    (Baylor College of Medicine (BCM)
    Baylor College of Medicine (BCM)
    The University of Texas MD Anderson Cancer Center)

  • San-Pin Wu

    (National Institute of Environmental Health Sciences (NIEHS))

  • Madhumita Ray

    (National Institute of Environmental Health Sciences (NIEHS))

  • Kyathanahalli S. Janardhan

    (Integrated Laboratory Systems)

  • Cynthia J. Willson

    (Integrated Laboratory Systems)

  • Sung-Nam Cho

    (BCM)

  • Patricia D. Castro

    (BCM)

  • Michael M. Ittmann

    (BCM)

  • Jian-Liang Li

    (National Institute of Environmental Health Sciences (NIEHS))

  • Roger J. Davis

    (University of Massachusetts Medical School
    University of Massachusetts Medical School)

  • Francesco J. DeMayo

    (National Institute of Environmental Health Sciences (NIEHS))

Abstract

Mechanisms of lung squamous cell carcinoma (LSCC) development are poorly understood. Here, we report that JNK1/2 activities attenuate Lkb1-deficiency-driven LSCC initiation and progression through repressing ΔNp63 signaling. In vivo Lkb1 ablation alone is sufficient to induce LSCC development by reducing MKK7 levels and JNK1/2 activities, independent of the AMPKα and mTOR pathways. JNK1/2 activities is positively regulated by MKK7 during LSCC development. Pharmaceutically elevated JNK1/2 activities abates Lkb1 dependent LSCC formation while compound mutations of Jnk1/2 and Lkb1 further accelerate LSCC progression. JNK1/2 is inactivated in a substantial proportion of human LSCC and JNK1/2 activities positively correlates with survival rates of lung, cervical and head and neck squamous cell carcinoma patients. These findings not only determine a suppressive role of the stress response regulators JNK1/2 on LSCC development by acting downstream of the key LSCC suppresser Lkb1, but also demonstrate activating JNK1/2 activities as a therapeutic approach against LSCC.

Suggested Citation

  • Jian Liu & Tianyuan Wang & Chad J. Creighton & San-Pin Wu & Madhumita Ray & Kyathanahalli S. Janardhan & Cynthia J. Willson & Sung-Nam Cho & Patricia D. Castro & Michael M. Ittmann & Jian-Liang Li & R, 2019. "JNK1/2 represses Lkb1-deficiency-induced lung squamous cell carcinoma progression," Nature Communications, Nature, vol. 10(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09843-1
    DOI: 10.1038/s41467-019-09843-1
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