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

Abstract

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. 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 () gene knockdown, and investigated the role of nuclear factor kappa B (NFκB) in CSCs during time-dependent Ca-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 Ca-ATPase (SERCA). 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. 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. .

Role of Mitochondria-Cytoskeleton Interactions in the Regulation of Mitochondrial Structure and Function in Cancer Stem Cells

“…Intracellular Ca 2+ level-dependent inhibition of mitochondrial motility occurs in response to spatial and temporal requirements and in order to enhance local Ca 2+ buffering. In a previous report, we showed that CSCs express sarco/endoplasmic reticulum Ca 2+ -ATPase to avoid apoptosis, which occurs after Ca 2+ overload under glucose deprived conditions [ 140 ]. How Ca 2+ -dependent mitochondrial movement in CSCs is accomplished is presently not well understood.…”

The Two-Way Relationship Between Calcium and Metabolism in Cancer

“…Furthermore, the therapeutic potential of the dual inhibition of glycolysis and Ca 2+ signaling should be considered. In support of this, combined treatment with a SERCA inhibitor (thapsigargin) and the glycolytic inhibitor 2-deoxy-d-glucose has recently shown significant anti-tumor effects in preclinical studies (Park et al, 2018).…”

“…Thus, the dual pharmacological modulation of Ca 2+ signaling and metabolism might have synergistic anticancer effects. Interestingly, preclinical evidence for the therapeutic potential of combined strategies is emerging (Park et al, 2018), yet it remains to be determined whether dual targeting will be effective in humans.…”

Patient-Derived, Drug-Resistant Colon Cancer Cells Evade Chemotherapeutic Drug Effects via the Induction of Epithelial-Mesenchymal Transition-Mediated Angiogenesis

“…RNA labeling and hybridization were performed using the Agilent One-Color Microarray-based Gene Expression Analysis protocol (Agilent Technologies, V 6.5, 2010). Additional protocol and data analysis details are described in our previous article [ 47 ].…”