Targeting PP2A inhibits the growth of triple-negative breast cancer cells
- 3 February 2020
- journal article
- research article
- Published by Taylor & Francis Ltd in Cell Cycle
- Vol. 19 (5), 592-600
- https://doi.org/10.1080/15384101.2020.1723195
Abstract
Triple-negative breast cancer (TNBC) does not respond to widely used targeted/endocrine therapies because of the absence of progesterone and estrogen receptors and HER2 amplification. It has been shown that the majority of TNBC cells are highly sensitive to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis, but the development of TRAIL resistance limits its efficacy. We previously found that protein phosphatase 2A (PP2A) plays an important role in TRAIL resistance. In this study, we evaluated the effects of PP2A inhibition on cell death in TRAIL-resistant TNBC cells. We found that the PP2A inhibitor LB-100 effectively inhibits the growth of a panel of TNBC cell lines including lines that are intrinsically resistant to TRAIL. Using two TRAIL-resistant cell lines generated from TRAIL-sensitive parental cells (MDA231 and SUM159), we found that both TRAIL-sensitive and -resistant cell lines are equally sensitive to LB-100. We also found that LB-100 sensitizes TNBC cells to clinically used chemotherapeutical agents, including paclitaxel and cisplatin. Importantly, we found that LB-100 effectively inhibits the growth of MDA468 tumors in mice in vivo without apparent toxicity. Collectively, these data suggest that pharmacological inhibition of PP2A activity could be a novel therapeutic strategy for treating patients with TNBC in a clinical setting.Keywords
Funding Information
- National Institutes of Health (R01CA174949)
- Wayne State University (Dean’s Diversity Fellowship)
This publication has 40 references indexed in Scilit:
- Identification of PP2A Complexes and Pathways Involved in Cell TransformationCancer Research, 2010
- Adjuvant therapy of triple negative breast cancerBreast Cancer Research and Treatment, 2010
- Triple-Negative Breast CancerThe Cancer Journal, 2010
- Inhibition of serine/threonine phosphatase PP2A enhances cancer chemotherapy by blocking DNA damage induced defense mechanismsProceedings of the National Academy of Sciences of the United States of America, 2009
- Cullin3-Based Polyubiquitination and p62-Dependent Aggregation of Caspase-8 Mediate Extrinsic Apoptosis SignalingCell, 2009
- TRAIL induces apoptosis in triple-negative breast cancer cells with a mesenchymal phenotypeBreast Cancer Research and Treatment, 2008
- A RNA Interference Screen Identifies the Protein Phosphatase 2A Subunit PR55γ as a Stress-Sensitive Inhibitor of c-SRCPLoS Genetics, 2007
- Death-receptor O-glycosylation controls tumor-cell sensitivity to the proapoptotic ligand Apo2L/TRAILNature Medicine, 2007
- Src kinase phosphorylates Caspase-8 on Tyr380: a novel mechanism of apoptosis suppressionThe EMBO Journal, 2006
- Overexpression of Bcl2 Blocks TNF-Related Apoptosis-Inducing Ligand (TRAIL)-Induced Apoptosis in Human Lung Cancer CellsBiochemical and Biophysical Research Communications, 2001