한빛사논문
- 조회429
In-Sung Song 1 †, Yu-Jeong Jeong 1 †, Jae Kwang Yun 2 †, Jimin Lee 1, Hae-Jun Yang 3, Young-Ho Park 3 4, Sun-Uk Kim 3 4, Seung-Mo Hong 5, Peter C W Lee 1, Geun Dong Lee 1 *, Sung-Wuk Jang 1 *
1Department of Biochemistry and Molecular Biology, Brain Korea 21 Project, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 138-736, Republic of Korea.
2Department of Thoracic and Cardiovascular Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 138-736, Republic of Korea.
3Futuristic Animal Resource & Research Center, Korea Research Institute of Bioscience and Biotechnology, Chungchenongbuk-do, 28116, Republic of Korea.
4Department of Functional Genomics, KRIBB, School of Bioscience, Korea University of Science and Technology (UST), Daejeon, 34113, Republic of Korea.
5Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 138-736, Republic of Korea.
†I.-S.S., Y.-J.J., and J.K.Y. contributed equally to this work.
*Corresponding authors: correspondence to Geun Dong Lee or Sung-Wuk Jang
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.
논문정보
- Research article
- 2024년 07월 (BRIC 등록일 2024-08-02)
- 국내 연구진
- 의약학 > 종양의학
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