ArticleAdvanced science (Weinheim, Baden-Wurttemberg, Germany)2024
TIPRL Regulates Stemness and Survival in Lung Cancer Stem Cells through CaMKK2-CaMK4-CREB Feedback Loop Activation.
Article in Advanced science (Weinheim, Baden-Wurttemberg, Germany), 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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5 citing papers in PubMed.
- The lysosomal cysteine protease cathepsin L promotes stemness and multidrug resistance of non-small cell lung cancer by targeting HGF activator.Molecular and cellular biochemistry · 2026Article
- Calhm6 Governs Macrophage Polarization Through Chp1-Camk4-Creb1 Axis and Ectosomal Delivery in Inflammatory Responses.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- PP2A Promotes the Symmetric Division of MUC1-Dominant Cancer Stem-Like Cells in Small Cell Lung Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Pan-cancer bioinformatics analysis of TIPRL in human tumors.Discover oncology · 2025Article
- TIPRL Regulates Stemness and Survival in Lung Cancer Stem Cells through CaMKK2-CaMK4-CREB Feedback Loop Activation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
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11 authors.
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Abstract
Frequent recurrence and metastasis caused by cancer stem cells (CSCs) are major challenges in lung cancer treatment. Therefore, identifying and characterizing specific CSC targets are crucial for the success of prospective targeted therapies. In this study, it is found that upregulated TOR Signaling Pathway Regulator-Like (TIPRL) in lung CSCs causes sustained activation of the calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) signaling pathway by binding to CaMKK2, thereby maintaining stemness and survival. CaMKK2-mediated activation of CaM kinase 4 (CaMK4) leads to phosphorylation of cAMP response element-binding protein (CREB) at Ser129 and Ser133, which is necessary for its maximum activation and the downstream constitutive expression of its target genes (Bcl2 and HMG20A). TIPRL depletion sensitizes lung CSCs to afatinib-induced cell death and reduces distal metastasis of lung cancer in vivo. It is determined that CREB activates the transcription of TIPRL in lung CSCs. The positive feedback loop consisting of CREB and TIPRL induces the sustained activation of the CaMKK2-CaMK4-CREB axis as a driving force and upregulates the expression of stemness- and survival-related genes, promoting tumorigenesis in patients with lung cancer. Thus, TIPRL and the CaMKK2 signaling axis may be promising targets for overcoming drug resistance and reducing metastasis in lung cancer.
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