제1저자 박기정(외과학교실, BK21졸 2012.8)
Clin Cancer Res. 2017 Dec 26. pii: clincanres.2219.2017. doi: 10.1158/1078-0432.CCR-17-2219. [Epub ahead of print]
Survival of cancer stem-like cells under metabolic stress via CaMK2α-mediated upregulation of sarco/endoplasmic reticulum calcium ATPase expression.
Park KC1, Kim SW2, Jeon JY3, Jo AR4, Choi HJ4, Kim JM5, Lee HG6, Kim Y7, Mills GB8, Noh SH9, Lee MG10, Park ES11, Cheong JH12.
1Department of Surgery, Yonsei University College of Medicine.2Severance Biomedical Science Institute, Yonsei University College of Medicine.3Nuclear Medicine, Yonsei University College of Medicine.4Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine.5Department of Medical science, Yonsei University College of Medicine.6Department of Microbiology and Immunology, Yonsei University College of Medicine.7Pharmacology, Yonsei University College of Medicine.8Departments of Systems Biology, The University of Texas MD Anderson Cancer Center.9Surgery, Yonsei University College of Medicine.10Department of Pharmacology, Yonsei University College of Medicine.11Medical convergence research institute, Yonsei University School of Medicine.12Surgery, Yonsei University College of Medicine firstname.lastname@example.org.
Cancer cells grow in an unfavorable metabolic milieu in the tumor microenvironment and are constantly exposed to metabolic stress such as chronic nutrient depletion. Cancer stem-like cells (CSCs) are intrinsically resistant to metabolic stress, thereby surviving nutrient insufficiency and driving more malignant tumor progression. In this study, we aimed to demonstrate the potential mechanisms by which CSCs avoid Ca2+-dependent apoptosis during glucose deprivation.
We investigated cell viability and apoptosis under glucose deprivation, performed genome-wide transcriptional profiling of paired CSCs and parental cells, studied the effect of calcium/calmodulin-dependent protein kinase 2 alpha (CaMK2α) gene knockdown, and investigated the role of nuclear factor kappa B (NFκB) in CSCs during time-dependent Ca2+-mediated and glucose deprivation-induced apoptosis. We also observed the effect of combined treatment with 2-deoxy-d-glucose, a metabolic inhibitor that mimics glucose deprivation conditions in mouse xenograft models, and thapsigargin, a specific inhibitor of SERCA.
We demonstrated the coordinated up-regulation of sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) in CSCs. SERCA, in turn, is transcriptionally regulated by CaMK2α via NFκB activation. Combined treatment with 2-deoxy-d-glucose and thapsigargin, a specific inhibitor of SERCA, significantly reduced tumor growth compared to that in untreated control animals or those treated with the metabolic inhibitor alone.
The current study provides compelling evidence that CaMK2α acts as a key anti-apoptosis regulator in metabolic stress-resistant CSCs by activating NFκB. The latter induces expression of SERCA, allowing survival in glucose-deprived conditions. Importantly, our combination therapeutic strategy provides a novel approach for the clinical application of CSC treatment.