TIPE2 sensitizes osteosarcoma cells to cis-platin by down-regulating MDR1 via the TAK1- NF-κB and - AP-1 pathways

Mol Immunol. 2018 Sep:101:471-478. doi: 10.1016/j.molimm.2018.08.010. Epub 2018 Aug 14.

Abstract

TIPE2 participates in multiple types of cancer development. However, its mechanism underlying chemoresistance in osteosarcoma has not been elucidated. Herein, we observed the expression of TIPE2 and MDR1 in cis-platin-resistant osteosarcoma tissues and cell lines. Compared to their matched sensitive cell lines and tissues, TIPE2 was downregulated while MDR1 expression was increased. Further investigation showed that overexpression of TIPE2 effectively inhibited MDR1 expression and greatly sensitized osteosarcoma cells to cis-platin, both in vivo and in vitro. Mechanistically, TIPE2 inhibited the transcription of the MDR1 promoter by interfering with the TAK1-NF-κB and -AP-1 pathways. Overall, our results elucidated for the first time that TIPE2 sensitizes osteosarcoma cells to cis-platin through downregulation of MDR1 and may be a novel target in osteosarcoma therapy.

Keywords: Cis-platin; MDR1; Osteosarcoma; TAK1; TIPE2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / genetics
  • Animals
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Cisplatin / pharmacology*
  • Down-Regulation* / drug effects
  • Gene Expression Regulation, Neoplastic / drug effects
  • HEK293 Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Mice, Inbred BALB C
  • Mice, Nude
  • NF-kappa B / metabolism*
  • Osteosarcoma / metabolism*
  • Osteosarcoma / pathology
  • Signal Transduction / drug effects
  • Transcription Factor AP-1 / metabolism*
  • Transcription, Genetic / drug effects

Substances

  • ABCB1 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • Intracellular Signaling Peptides and Proteins
  • NF-kappa B
  • TNFAIP8L2 protein, human
  • Transcription Factor AP-1
  • Cisplatin