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

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Abstract

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.

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Abbreviations

BAPTA-AM:

1,2-Bis(o-aminophenoxy)ethane-N,N,N’,N’,-tetraacetic acid tetra-(acetoxymethyl)-ester

HIF-1α:

Hypoxia-inducible factor 1α

PI3K:

Phosphoinositide 3-kinase

Tg:

Thapsigargin

Iono:

Ionomycin

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Acknowledgments

Olga Mavrofrydi is supported by the National Scholarships Foundation of Greece. This work was partially supported by the Special Account for Research Grants of the National and Kapodistrian University of Athens.

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  1. Georgios Divolis

    Present address: Center for Clinical, Experimental Surgery & Translational Research, Biomedical Research Foundation, Academy of Athens, Soranou Efesiou 4, 11527, Athens, Greece

Authors and Affiliations

  1. Division of Animal and Human Physiology, Department of Biology, National and Kapodistrian University of Athens, Panepistimiopolis, 15784, Athens, Greece

    Georgios Divolis, Panagiota Mavroeidi, Olga Mavrofrydi & Panagiota Papazafiri

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  1. Georgios Divolis
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  2. Panagiota Mavroeidi
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Correspondence to Panagiota Papazafiri.

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Divolis, G., Mavroeidi, P., Mavrofrydi, O. et al. Differential effects of calcium on PI3K-Akt and HIF-1α survival pathways. Cell Biol Toxicol 32, 437–449 (2016). https://doi.org/10.1007/s10565-016-9345-x

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