PMCA2 silencing potentiates MDA-MB-231 breast cancer cell death initiated with the Bcl-2 inhibitor ABT-263

Biochem Biophys Res Commun. 2016 Sep 30;478(4):1792-7. doi: 10.1016/j.bbrc.2016.09.030. Epub 2016 Sep 7.

Abstract

PMCA2 overexpression in some breast cancers suggests that this calcium pump isoform may play a role in breast pathophysiology. To investigate PMCA2 as a potential drug target for breast cancer therapy, we assessed the functional consequence of PMCA2 silencing on cell death pathways and calcium signals in the basal-like MDA-MB-231 breast cancer cell line. Silencing PMCA2 expression alone has no effect on MDA-MB-231 cell viability, however, PMCA2 silencing promotes calcium-induced cell death initiated with the calcium ionophore ionomycin. Assessment of cytoplasmic calcium responses generated with various agents including ionomycin demonstrates that in MDA-MB-231 cells, PMCA2 does not play a major role in shaping global calcium signals. We also examined the ability of PMCA2 silencing to modulate caspase-dependent cell death triggered by a Bcl-2 inhibitor that is in clinical development for the treatment of various cancers, ABT-263 (Navitoclax). Despite the lack of effect on global calcium responses, PMCA2 silencing augmented Bcl-2 inhibitor (ABT-263)-mediated MDA-MB-231 breast cancer cell death. These studies provide evidence that PMCA2 inhibitors could sensitize PMCA2-positive breast cancers to cell death initiators that work through mechanisms involving the Bcl-2 survival pathway.

Keywords: ABT-263; Breast cancer; Calcium; Cell death; Ionomycin; PMCA2.

MeSH terms

  • Aniline Compounds / pharmacology*
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects*
  • Apoptosis / genetics
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Calcium / metabolism
  • Calcium Ionophores / pharmacology
  • Caspases / metabolism
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • Dose-Response Relationship, Drug
  • Humans
  • Ionomycin / pharmacology
  • Microscopy, Fluorescence
  • Plasma Membrane Calcium-Transporting ATPases / genetics*
  • Plasma Membrane Calcium-Transporting ATPases / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • RNA Interference*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sulfonamides / pharmacology*

Substances

  • Aniline Compounds
  • Antineoplastic Agents
  • Calcium Ionophores
  • Proto-Oncogene Proteins c-bcl-2
  • Sulfonamides
  • Ionomycin
  • Caspases
  • Plasma Membrane Calcium-Transporting ATPases
  • ATP2B2 protein, human
  • Calcium
  • navitoclax