JNK<sup>1/2</sup> represses Lkb<sup>1</sup>-deficiency-induced lung squamous cell carcinoma progression.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 31089135.
- Also identified by DOI 10.1038/s41467-019-09843-1 and PMC identifier 6517592.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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.
Medical subject headings
- Carcinoma, Squamous Cell
- Lung Neoplasms
- Mitogen-Activated Protein Kinase 8
- Mitogen-Activated Protein Kinase 9
- Protein Serine-Threonine Kinases