@article{01810230f83840238027f5b027b9da38,
title = "Survival of cancer stem-like cells under metabolic stress via camk2a-mediated upregulation of sarco/endoplasmic reticulum calcium atpase expression",
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{\th}-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 (CaMK2a) gene knockdown, and investigated the role of nuclear factor kappa B (NFkB) in CSCs during time-dependent Ca2{\th}-mediated and glucose deprivation–induced apoptosis. We also observed the effect of combined treatment with 2-deoxy-D-glu-cose, a metabolic inhibitor that mimics glucose deprivation conditions in mouse xenograft models, and thapsigargin, a specific inhibitor of sarco/endoplasmic reticulum Ca2{\th}-ATPase (SERCA). Results: We demonstrated the coordinated upregulation of SERCA in CSCs. SERCA, in turn, is transcriptionally regulated by CaMK2a via NFkB 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 CaMK2a acts as a key antiapoptosis regulator in metabolic stress-resistant CSCs by activating NFkB. 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.",
author = "Park, {Ki Cheong} and Kim, {Seung Won} and Jeon, {Jeong Yong} and {Ra Jo}, A. and Choi, {Hye Ji} and Jungmin Kim and Lee, {Hyun Gyu} and Yonjung Kim and Mills, {Gordon B.} and Noh, {Sung Hoon} and Lee, {Min Goo} and Park, {Eun Sung} and Cheong, {Jae Ho}",
note = "Funding Information: We thank Sang Yong Kim for assistance with the confocal microscopy to measure cytosolic calcium concentration and for critical reading of the manuscript. This work was supported by grants from the National Research Foundation of Korea (NRF) funded by the Korean government (MSIP; no. NRF-2011-0030086) and Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare (no. HI14C1324) and Faculty Research Grant funded by Yonsei University College of Medicine (6-2010-0153; all to J.-H. Cheong). M.G. Lee was supported by a grant from the NRF (no. 2013R1A3A2042197). Funding Information: G.B. Mills has ownership interests (including patents) at Catena Pharmaceuticals, ImmunoMet, Myriad Genetics, PTV Ventures and Spindletop Ventures, reports receiving speakers bureau honoraria from Allostery, AstraZeneca, ImmunoMet, ISIS Pharmaceuticals, Lilly, MedImmune, Novartis, Pfizer, Sym-phogen, and Tarveda, is a consultant/advisory board member for Adventist Health, Allostery, AstraZeneca, Catena Pharmaceuticals, Critical Outcome Technologies, ImmunoMet, ISIS Pharmaceuticals, Lilly, MedImmune, Novartis, Precision Medicine, Provista Diagnostics, Signalchem Lifesciences, Symphogen, Takeda/Millennium Pharmaceuticals, Tarveda, and Tau Therapeutics, and reports receiving commercial research grants from Adelson Medical Research Foundation, AstraZeneca, Breast Cancer Research Foundation, Critical Outcome Technologies, Illumina, Karus, Komen Research Foundation, Nanostring, Pfizer, Takeda/Millennium Pharmaceuticals. No potential conflicts of interest were disclosed by the other authors. Publisher Copyright: {\textcopyright} 2017 American Association for Cancer Research.",
year = "2018",
month = apr,
day = "1",
doi = "10.1158/1078-0432.CCR-17-2219",
language = "English (US)",
volume = "24",
pages = "1677--1690",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "7",
}