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Dual mechanisms of sHA 14-1 in inducing cell death through endoplasmic reticulum and mitochondria

David Hermanson1, Sadiya N Addo, Anna A Bajer

  • 1Department of Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota, USA.

Molecular Pharmacology
|June 30, 2009
PubMed

Insights

A novel stable analog of HA 14-1 (sHA 14-1) exhibits a unique dual-action mechanism, targeting both Bcl-2 proteins and SERCA pumps. This dual action promotes apoptosis in cancer cells by disrupting ER calcium homeostasis and mitochondrial function.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • The small molecule HA 14-1 is a Bcl-2 antagonist promoting apoptosis in cancer cells, but its mechanism is unclear.
  • HA 14-1 has a short in vitro half-life, necessitating the development of a stable analog (sHA 14-1).

Purpose of the Study:

  • To characterize the mode of action of the stable HA 14-1 analog (sHA 14-1).
  • To evaluate the effects of sHA 14-1 on the endoplasmic reticulum (ER) and mitochondria, key organelles involved in apoptosis regulation.

Main Methods:

  • Assessed ER calcium release and ATF4 induction in human leukemic cells.
  • Investigated direct inhibition of sarcoendoplasmic reticulum Ca(2+)-ATPase (SERCA) and inositol triphosphate receptors.
  • Evaluated mitochondrial transmembrane potential (Δpsi m) loss and caspase-9 activation.
  • Compared sHA 14-1 effects with thapsigargin and ABT-737, and assessed protection by a pan-caspase inhibitor.

Main Results:

  • sHA 14-1 rapidly induced ER calcium release and ATF4 induction, similar to thapsigargin but with distinct kinetics.
  • sHA 14-1 directly inhibited SERCA activity but not the inositol triphosphate receptor.
  • sHA 14-1 triggered mitochondrial dysfunction (Δpsi m loss) and caspase-9 activation, unlike thapsigargin.
  • ABT-737, a known Bcl-2 antagonist, affected mitochondria but not the ER.

Conclusions:

  • sHA 14-1 exhibits a unique dual-targeting mechanism against tumor cell apoptotic resistance.
  • It targets both antiapoptotic Bcl-2 family proteins and SERCA proteins.
  • This dual action contributes to its ability to induce apoptosis in malignant cells.

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