The GEF-H1/PKD3 signaling pathway promotes the maintenance of triple-negative breast cancer stem cells

Int J Cancer. 2020 Jun 15;146(12):3423-3434. doi: 10.1002/ijc.32798. Epub 2019 Dec 14.

Abstract

Protein kinase D3 (PKD3) is upregulated in triple-negative breast cancer (TNBC) and associated with cell proliferation and metastasis development but its precise pro-oncogenic function is unknown. Here we show that PKD3 is required for the maintenance of the TNBC stem cell population. The depletion of PKD3 in MDA-MB-231 cells reduced the cancer stem cell frequency in vitro and tumor initiation potential in vivo. We further provide evidence that the RhoGEF GEF-H1 is upstream of PKD3 activation in TNBC stem cells. Most importantly, pharmacological PKD inhibition in combination with paclitaxel synergistically decreased oncosphere and colony formation efficiency in vitro and tumor recurrence in vivo. Based on our results we propose that targeting the GEF-H1/PKD3 signaling pathway in combination with chemotherapy might provide an effective therapeutic option for TNBC.

Keywords: ALDH; PKD3; TNBC; cancer stem cells; paclitaxel.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Movement / genetics
  • Cell Proliferation / drug effects
  • Cell Survival
  • Drug Synergism
  • Female
  • Gene Knockdown Techniques
  • Humans
  • Mice
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / pathology*
  • Paclitaxel / pharmacology
  • Paclitaxel / therapeutic use
  • Protein Kinase C / antagonists & inhibitors
  • Protein Kinase C / genetics
  • Protein Kinase C / metabolism*
  • Pyrimidines / pharmacology
  • Pyrimidines / therapeutic use
  • Rho Guanine Nucleotide Exchange Factors / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Triple Negative Breast Neoplasms / drug therapy
  • Triple Negative Breast Neoplasms / pathology*
  • Xenograft Model Antitumor Assays

Substances

  • ARHGEF2 protein, human
  • CRT 0066101
  • Pyrimidines
  • Rho Guanine Nucleotide Exchange Factors
  • protein kinase C nu
  • Protein Kinase C
  • Paclitaxel