Survival of cancer stem-like cells under metabolic stress via camk2a-mediated upregulation of sarco/endoplasmic reticulum calcium atpase expression

Ki Cheong Park, Seung Won Kim, Jeong Yong Jeon, A. Ra Jo, Hye Ji Choi, Jungmin Kim, Hyun Gyu Lee, Yonjung Kim, Gordon Mills, Sung Hoon Noh, Min Goo Lee, Eun Sung Park, Jae Ho Cheong

Research output: Contribution to journalArticle

6 Citations (Scopus)

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 Ca-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 Ca-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 Ca-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.

Original languageEnglish (US)
Pages (from-to)1677-1690
Number of pages14
JournalClinical Cancer Research
Volume24
Issue number7
DOIs
StatePublished - Apr 1 2018
Externally publishedYes

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Sarcoplasmic Reticulum Calcium-Transporting ATPases
Physiological Stress
Neoplastic Stem Cells
Calcium-Transporting ATPases
Endoplasmic Reticulum
Up-Regulation
Calcium-Calmodulin-Dependent Protein Kinases
NF-kappa B
Glucose
Thapsigargin
Apoptosis
Gene Knockdown Techniques
Food
Neoplasms
Tumor Microenvironment
Deoxyglucose
Heterografts
Cell Survival
Research Design
Genome

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Survival of cancer stem-like cells under metabolic stress via camk2a-mediated upregulation of sarco/endoplasmic reticulum calcium atpase expression. / Park, Ki Cheong; Kim, Seung Won; Jeon, Jeong Yong; Ra Jo, A.; Choi, Hye Ji; Kim, Jungmin; Lee, Hyun Gyu; Kim, Yonjung; Mills, Gordon; Noh, Sung Hoon; Lee, Min Goo; Park, Eun Sung; Cheong, Jae Ho.

In: Clinical Cancer Research, Vol. 24, No. 7, 01.04.2018, p. 1677-1690.

Research output: Contribution to journalArticle

Park, KC, Kim, SW, Jeon, JY, Ra Jo, A, Choi, HJ, Kim, J, Lee, HG, Kim, Y, Mills, G, Noh, SH, Lee, MG, Park, ES & Cheong, JH 2018, 'Survival of cancer stem-like cells under metabolic stress via camk2a-mediated upregulation of sarco/endoplasmic reticulum calcium atpase expression', Clinical Cancer Research, vol. 24, no. 7, pp. 1677-1690. https://doi.org/10.1158/1078-0432.CCR-17-2219
Park, Ki Cheong ; Kim, Seung Won ; Jeon, Jeong Yong ; Ra Jo, A. ; Choi, Hye Ji ; Kim, Jungmin ; Lee, Hyun Gyu ; Kim, Yonjung ; Mills, Gordon ; Noh, Sung Hoon ; Lee, Min Goo ; Park, Eun Sung ; Cheong, Jae Ho. / Survival of cancer stem-like cells under metabolic stress via camk2a-mediated upregulation of sarco/endoplasmic reticulum calcium atpase expression. In: Clinical Cancer Research. 2018 ; Vol. 24, No. 7. pp. 1677-1690.
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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.",
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T1 - Survival of cancer stem-like cells under metabolic stress via camk2a-mediated upregulation of sarco/endoplasmic reticulum calcium atpase expression

AU - Park, Ki Cheong

AU - Kim, Seung Won

AU - Jeon, Jeong Yong

AU - Ra Jo, A.

AU - Choi, Hye Ji

AU - Kim, Jungmin

AU - Lee, Hyun Gyu

AU - Kim, Yonjung

AU - Mills, Gordon

AU - Noh, Sung Hoon

AU - Lee, Min Goo

AU - Park, Eun Sung

AU - Cheong, Jae Ho

PY - 2018/4/1

Y1 - 2018/4/1

N2 - 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 Ca2þ-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 Ca2þ-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 Ca2þ-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.

AB - 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 Ca2þ-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 Ca2þ-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 Ca2þ-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.

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