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Sep, 2024;11 (36): e2406309.

TIPRL Regulates Stemness and Survival in Lung Cancer Stem Cells through CaMKK2-CaMK4-CREB Feedback Loop Activation.

In-Sung Song, Yu-Jeong Jeong, Jae Kwang Yun, Jimin Lee, Hae-Jun Yang, Young-Ho Park, Sun-Uk Kim, Seung-Mo Hong, Peter C W Lee, Geun Dong Lee, Sung-Wuk Jang
Author Information
  1. In-Sung Song: Department of Biochemistry and Molecular Biology, Brain Korea 21 Project, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 138-736, Republic of Korea.
  2. Yu-Jeong Jeong: Department of Biochemistry and Molecular Biology, Brain Korea 21 Project, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 138-736, Republic of Korea.
  3. Jae Kwang Yun: Department of Thoracic and Cardiovascular Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 138-736, Republic of Korea.
  4. Jimin Lee: Department of Biochemistry and Molecular Biology, Brain Korea 21 Project, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 138-736, Republic of Korea.
  5. Hae-Jun Yang: Futuristic Animal Resource & Research Center, Korea Research Institute of Bioscience and Biotechnology, Chungchenongbuk-do, 28116, Republic of Korea.
  6. Young-Ho Park: Futuristic Animal Resource & Research Center, Korea Research Institute of Bioscience and Biotechnology, Chungchenongbuk-do, 28116, Republic of Korea.
  7. Sun-Uk Kim: Futuristic Animal Resource & Research Center, Korea Research Institute of Bioscience and Biotechnology, Chungchenongbuk-do, 28116, Republic of Korea.
  8. Seung-Mo Hong: Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 138-736, Republic of Korea.
  9. Peter C W Lee: Department of Biochemistry and Molecular Biology, Brain Korea 21 Project, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 138-736, Republic of Korea.
  10. Geun Dong Lee: Department of Biochemistry and Molecular Biology, Brain Korea 21 Project, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 138-736, Republic of Korea.
  11. Sung-Wuk Jang: Department of Biochemistry and Molecular Biology, Brain Korea 21 Project, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 138-736, Republic of Korea. ORCID
PMID: 39076120 DOI: 10.1002/advs.202406309

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.

Keywords

CaMKK2���CaMK4���CREB feedback loop activation TIPRL cancer stem cell drug resistance lung cancer metastasis

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Grants

  1. 2022R1A2B5B01001782/Ministry of Education, Science and Technology
  2. 2020R1A6A3A01098464/Ministry of Education

MeSH Term

Calcium-Calmodulin-Dependent Protein Kinase Kinase
Lung Neoplasms
Humans
Neoplastic Stem Cells
Mice
Animals
Signal Transduction
Cyclic AMP Response Element-Binding Protein
Calcium-Calmodulin-Dependent Protein Kinase Type 4
Cell Line, Tumor
Feedback, Physiological
Disease Models, Animal

Chemicals

Calcium-Calmodulin-Dependent Protein Kinase Kinase
CAMKK2 protein, human
Cyclic AMP Response Element-Binding Protein
Calcium-Calmodulin-Dependent Protein Kinase Type 4
CAMK4 protein, human
CREB1 protein, human
Journal Article
Article has an altmetric score of 1

Word Cloud

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