Coupling of mitochondria to store-operated Ca2+-signaling sustains constitutive activation of protein kinase B/Akt and augments survival of malignant melanoma cells

Ben Feldman, Shlomit Fedida-Metula, Julia Nita, Israel Sekler, Daniel Fishman

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

Abstract

Mitochondria are emerging as a major hub for cellular Ca2+-signaling, though their contribution to Ca2+-driven growth- and survival-promoting events in cancer is poorly understood. Here employing flow cytometry to monitor mitochondrial and cytosolic Ca2+, we assessed trans-mitochondrial Ca2+-transport and store-operated Ca2+-influx (store-operated channels (SOC)) in malignant vs. non-malignant B16BL6 melanoma clones. Remarkably, mitochondrial Ca2+-fluxes measured in whole cells or in isolated mitochondria were accelerated in the malignant clones compared to their non-malignant counterpart clones. This coincided with enhanced SOC-mediated Ca2+-influx and high levels of constitutively active protein kinase B/Akt (PKB). Interruption of trans-mitochondrial Ca2+-transport in the malignant cells with an antagonist of the mitochondrial Na+/Ca2+ exchanger, CGP-37157, abolsihed SOC-mediated Ca2+-influx, inactivated PKB, retarded cell growth and increased vulnerability to apoptosis. Similarly, direct SOC blockade by silencing Stim1 inhibited PKB, indicating that the crosstalk between SOC and mitochondria is essential to preserve PKB in constitutively active state. Finally, the retraction of mitochondria from sub-plasmalemmal micro-domains triggered by Fis1 over-expression inhibited SOC-coupled trans-mitochondrial Ca2+-flux, Ca2+-entry via SOC and PKB activity. Taken together, our data show that in the malignant melanoma cells, the functional and spatial relationship of up-regulated mitochondrial Ca2+-transport to the SOC sustains the robust Ca2+-responses and down-stream signaling critical for apoptosis-resistance and proliferation.

Original languageEnglish
Pages (from-to)525-537
Number of pages13
JournalCell Calcium
Volume47
Issue number6
DOIs
StatePublished - 1 Jan 2010

Keywords

  • Apoptosis
  • Calcium
  • Melanoma
  • Mitochondrium
  • PKB

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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