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

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^2þ-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^2þ-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^2þ-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.