HOXB4 knockdown enhances the cytotoxic effect of paclitaxel and cisplatin by downregulating ABC transporters in ovarian cancer cells

Gene. 2018 Jul 15:663:9-16. doi: 10.1016/j.gene.2018.04.033. Epub 2018 Apr 14.

Abstract

Therapeutic effects of anti-cancer drugs for ovarian cancer were limited due to the rapid development of chemotherapy resistance. The aim of this study was to test whether knockdown of Homeobox B4 (HOXB4) enhanced the cytotoxic effect of paclitaxel and cisplatin in ovarian cancer cells. HOXB4 expressions at mRNA and protein levels were upregulated in Taxol-resistant A2780 (A2780/Taxol) and DDP-resistant SKOV-3 (SKOV-3/DDP) cells. HOXB4 knockdown enhanced the cytotoxic effects of Taxol and DDP in A2780/Taxol and SKOV-3/DDP cells, respectively. HOXB4 silencing suppressed the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway and reduced the expression of ABCB1, ABCC1 and ABCG2 in ovarian cancer cells. PI3K inhibitor LY294002 or siRNA targeting Akt (si-Akt) treatment inhibited cell viability, decreased protein levels of ABCB1, ABCC1 and ABCG2, and increased LDH release in A2780/Taxol and SKOV-3/DDP cells. These findings revealed that HOXB4 knockdown enhanced the cytotoxic effects of Taxol and DDP by downregulating ABC transporters via inhibiting the PI3K/Akt pathway in ovarian cancer cells.

Keywords: ATP-binding cassette transporters; Cisplatin; HOXB4; Ovarian cancer; PI3K/Akt pathway; Paclitaxel.

MeSH terms

  • ATP-Binding Cassette Transporters / metabolism*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Cisplatin / pharmacology*
  • Down-Regulation
  • Drug Resistance, Neoplasm*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Gene Knockdown Techniques*
  • Homeodomain Proteins / genetics*
  • Homeodomain Proteins / metabolism
  • Humans
  • Ovarian Neoplasms / drug therapy
  • Ovarian Neoplasms / genetics*
  • Ovarian Neoplasms / metabolism
  • Paclitaxel / pharmacology*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Up-Regulation

Substances

  • ATP-Binding Cassette Transporters
  • HOXB4 protein, human
  • Homeodomain Proteins
  • Transcription Factors
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • Paclitaxel
  • Cisplatin