Differential effects of calcium on PI3K-Akt and HIF-1α survival pathways

Cell Biol Toxicol. 2016 Oct;32(5):437-49. doi: 10.1007/s10565-016-9345-x. Epub 2016 Jun 25.


Calcium signaling participates in the regulation of numberless cellular functions including cell cycle progression and cellular migration, important processes for cancer expansion. Cancer cell growth, migration, and invasion are typically supported by PI3K/Akt activation, while a hypoxic environment is critical in cancer development. Accordingly, in the present study, we aimed at investigating whether perturbations in calcium homeostasis induce alterations of HIF-1α and activate Akt levels in epithelial A549 and A431 cells. Survival was drastically reduced in the presence of calcium chelator BAPTA-AM and thapsigargin, a SERCA inhibitor inducing store-operated calcium entry, to a lesser extent. Calcium chelation provoked a transient but strong upregulation of HIF-1α protein levels and accumulation in the nucleus, whereas in the presence of thapsigargin, HIF-1α levels were rapidly abolished before reaching and exceeding control levels. Despite cell death, calcium chelation merely inhibited Akt, which was significantly activated in the presence of thapsigargin. Moreover, when store-operated calcium entry was simulated by reintroducing calcium ions in cell suspensions, Akt was rapidly activated in the absence of any growth factor. These data further underscore the growing importance of calcium entry and directly link this elementary event of calcium homeostasis to the Akt pathway, which is commonly deregulated in cancer.

Keywords: Akt kinase; Calcium; Cancer; Epithelial; Hypoxia-inducible factor 1; Thapsigargin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Alveolar Epithelial Cells / drug effects
  • Alveolar Epithelial Cells / enzymology
  • Alveolar Epithelial Cells / metabolism*
  • Calcium / metabolism*
  • Calcium Signaling
  • Cell Line, Tumor
  • Chelating Agents / pharmacology
  • Egtazic Acid / analogs & derivatives
  • Egtazic Acid / pharmacology
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Intercellular Signaling Peptides and Proteins / pharmacology
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Thapsigargin / pharmacology
  • Transcriptional Activation


  • Chelating Agents
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Intercellular Signaling Peptides and Proteins
  • 1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester
  • Egtazic Acid
  • Thapsigargin
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • Calcium