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Ouabain targets the unfolded protein response for selective killing of HepG2 cells during glucose deprivation

Tulay Ozdemir1, Rukiye Nar, Veli Kilinc

  • 1Gazi State Hospital, Samsun, Turkey.

Cancer Biotherapy & Radiopharmaceuticals
|July 5, 2012
PubMed

Insights

Ouabain disrupts the unfolded protein response (UPR) in glucose-deprived cancer cells, selectively inducing cell death. This suggests UPR disruption is a promising strategy for developing novel cancer therapies.

Area of Science:

  • Cell Biology
  • Biochemistry
  • Cancer Research

Background:

  • Ouabain is a cardiotonic steroid that inhibits the Na(+)/K(+)-ATPase.
  • The precise relationship between ouabain and the unfolded protein response (UPR) remains unclear.
  • Investigating ouabain's effects on cell proliferation, apoptosis, and UPR is crucial.

Purpose of the Study:

  • To investigate the effects of ouabain on HepG2 cell proliferation, apoptosis, and UPR.
  • To determine if ouabain modulates the UPR transcription program.
  • To explore the potential of ouabain in cancer treatment, particularly under glucose-deprived conditions.

Main Methods:

  • HepG2 cells were treated with varying concentrations of ouabain (0.75–750 nM) with or without 2-deoxyglucose (2-DG).
  • Real-time PCR was used to quantify the expression of UPR-related genes (Grp78, Grp94, CHOP) and other relevant genes (MTJ-1, HKII, MDR-1, MRP-1, HO-1, Par-4).
  • Cell number, viability, and proliferation were monitored using the xCELLigence real-time cell analyzer system.

Main Results:

  • Ouabain treatment modulated the UPR transcription program in HepG2 cells.
  • Ouabain induced cell death in glucose-deprived tumor cells.
  • Ouabain exhibited no cytotoxicity at tested concentrations in normal conditions but was effective under 2-DG stress.

Conclusions:

  • Disrupting the UPR during glucose deprivation offers a potential strategy for selective cancer cell killing.
  • Ouabain's ability to modulate UPR provides a chemical basis for developing UPR-targeting drugs against solid tumors.
  • Ouabain warrants further investigation as an adjunct therapy for conventional cancer treatment.

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