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Targeting PP2A inhibits the growth of triple-negative breast cancer cells

Mohammed Hafiz Uddin1, Julio M Pimentel1,2, Madhumita Chatterjee1

  • 1Department of Oncology and Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA.

Cell Cycle (Georgetown, Tex.)
|February 4, 2020
PubMed

Insights

Inhibiting protein phosphatase 2A (PP2A) with LB-100 effectively kills triple-negative breast cancer (TNBC) cells, including resistant types. This approach also enhances chemotherapy efficacy and shows promise in preclinical models.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Triple-negative breast cancer (TNBC) lacks targeted therapy options due to absent hormone receptors and HER2 amplification.
  • While TNBC cells are sensitive to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), TRAIL resistance limits its clinical use.
  • Protein phosphatase 2A (PP2A) has been identified as a key mediator of TRAIL resistance in TNBC.

Purpose of the Study:

  • To investigate the therapeutic potential of inhibiting PP2A activity in TRAIL-resistant TNBC.
  • To evaluate the efficacy of the PP2A inhibitor LB-100 in TNBC cell lines and in vivo models.

Main Methods:

  • Treatment of TNBC cell lines with the PP2A inhibitor LB-100.
  • Assessment of cell viability and apoptosis in response to LB-100, TRAIL, paclitaxel, and cisplatin.
  • In vivo studies using mouse models bearing TNBC xenografts.

Main Results:

  • LB-100 demonstrated potent growth inhibition across a panel of TNBC cell lines, including those intrinsically resistant to TRAIL.
  • Both TRAIL-sensitive and TRAIL-resistant TNBC cells exhibited similar sensitivity to LB-100.
  • LB-100 enhanced the efficacy of paclitaxel and cisplatin in TNBC cells.
  • LB-100 effectively suppressed MDA468 tumor growth in mice with no observed toxicity.

Conclusions:

  • Pharmacological inhibition of PP2A via LB-100 represents a promising novel therapeutic strategy for TNBC.
  • Targeting PP2A may overcome TRAIL resistance and enhance the effectiveness of conventional chemotherapeutics in TNBC treatment.
Keywords:
PP2A inhibitorTNBCTRAILapoptosis

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