AGPAT9 suppresses cell growth, invasion and metastasis by counteracting acidic tumor microenvironment through KLF4/LASS2/V-ATPase signaling pathway in breast cancer

Oncotarget. 2015 Jul 30;6(21):18406-17. doi: 10.18632/oncotarget.4074.

Abstract

Human 1-acylglycerol-3-phosphate O-acyltransferase 9 (AGPAT9) is the gene identified from adipose tissue in 2007. We found AGPAT9 expression was significantly higher in poorly invasive MCF7 human breast cancer cells than the highly invasive MDA-MB-231 cells. AGPAT9 significantly inhibited the proliferation of breast cancer cells in vitro and in vivo. Live-cell imaging and transwell assays showed that AGPAT9 could significantly inhibit the migration and invasive capacities of breast cancer cells. The inhibitory effect of AGPAT9 on metastasis was also observed in vivo in lung metastasis model. AGPAT9 inhibited breast cancer cell proliferation, migration and invasion through, at least in part, suppressing the V-ATPase activity. In addition, increased AGPAT9 expression in MCF-7/ADR cells could increase the chemosensitivity to doxorubicin (Dox). Our findings suggest that increasing AGPAT9 expression may be a new approach that can be used for breast cancer treatment.

Keywords: AGPAT9; acidic tumor microenvironment; breast cancer; invasion; proliferation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Acylglycerol-3-Phosphate O-Acyltransferase / genetics*
  • 1-Acylglycerol-3-Phosphate O-Acyltransferase / metabolism
  • Animals
  • Antibiotics, Antineoplastic / pharmacology
  • Blotting, Western
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Proliferation / genetics*
  • Doxorubicin / pharmacology
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Hydrogen-Ion Concentration
  • Kruppel-Like Factor 4
  • Kruppel-Like Transcription Factors / genetics*
  • Kruppel-Like Transcription Factors / metabolism
  • MCF-7 Cells
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Mice, Inbred BALB C
  • Mice, Nude
  • Microscopy, Confocal
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • RNA Interference
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Sphingosine N-Acyltransferase / genetics*
  • Sphingosine N-Acyltransferase / metabolism
  • Transplantation, Heterologous
  • Tumor Microenvironment / drug effects
  • Tumor Microenvironment / genetics*
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / metabolism
  • Vacuolar Proton-Translocating ATPases / genetics*
  • Vacuolar Proton-Translocating ATPases / metabolism

Substances

  • ATP6V0C protein, human
  • Antibiotics, Antineoplastic
  • KLF4 protein, human
  • Klf4 protein, mouse
  • Kruppel-Like Factor 4
  • Kruppel-Like Transcription Factors
  • Membrane Proteins
  • Tumor Suppressor Proteins
  • Doxorubicin
  • CERS2 protein, human
  • Sphingosine N-Acyltransferase
  • 1-Acylglycerol-3-Phosphate O-Acyltransferase
  • GPAT3 protein, human
  • Vacuolar Proton-Translocating ATPases