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Survival of Cancer Stem-Like Cells Under Metabolic Stress via CaMK2α-mediated Upregulation of Sarco/Endoplasmic Reticulum Calcium ATPase Expression

Authors
 Ki Cheong Park  ;  Seung Won Kim  ;  Jeong Yong Jeon  ;  A. Ra Jo  ;  Hye Ji Choi  ;  Jungmin Kim  ;  Hyun Gyu Lee  ;  Yonjung Kim  ;  Gordon B. Mills  ;  Sung Hoon Noh  ;  Min Goo Lee  ;  Eun Sung Park  ;  Jae-Ho Cheong 
Citation
 Clinical Cancer Research, Vol.24(7) : 1677-1690, 2018 
Journal Title
 Clinical Cancer Research 
ISSN
 1078-0432 
Issue Date
2018
Abstract
Purpose: 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 (CSC) 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.Experimental Design: 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 sarco/endoplasmic reticulum Ca2+-ATPase (SERCA).Results: We demonstrated the coordinated upregulation of 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 with that in untreated control animals or those treated with the metabolic inhibitor alone.Conclusions: The current study provides compelling evidence that CaMK2α acts as a key antiapoptosis 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.
Full Text
http://clincancerres.aacrjournals.org/content/24/7/1677.long
DOI
10.1158/1078-0432.CCR-17-2219
Appears in Collections:
1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실)
1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실)
Yonsei Authors
김연정(Kim, Yon Jung) ORCID logo https://orcid.org/0000-0003-0251-8711
노성훈(Noh, Sung Hoon) ORCID logo https://orcid.org/0000-0003-4386-6886
박기청(Park, Ki Cheong) ORCID logo https://orcid.org/0000-0002-3435-3985
이민구(Lee, Min Goo) ORCID logo https://orcid.org/0000-0001-7436-012X
정재호(Cheong, Jae Ho)
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URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/161790
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