Protein phosphatase complex PP5/PPP2R3C dephosphorylates P-glycoprotein/ABCB1 and down-regulates the expression and function

Cancer Lett. 2014 Apr 1;345(1):124-31. doi: 10.1016/j.canlet.2013.12.007. Epub 2013 Dec 11.

Abstract

P-glycoprotein (P-gp)/ABCB1 is a key molecule of multidrug resistance in cancer. Protein phosphatase (PP) 2A, regulatory subunit B, gamma (PPP2R3C), which is a regulatory subunit of PP2A and PP5, was identified as a binding candidate to P-gp. Immunoprecipitation-western blotting revealed that PP5 and PPP2R3C were coprecipitated with P-gp, while PP2A was not. PP5/PPP2R3C dephosphorylated protein kinase A/protein kinase C-phosphorylation of P-gp. Knockdown of PP5 and/or PPP2R3C increased P-gp expression and lowered the sensitivity to vincristine and doxorubicin. Consequently, our results indicate that PP5/PPP2R3C negatively regulates P-gp expression and function.

Keywords: Dephosphorylation; P-glycoprotein/ABCB1; PP5; PPP2R3C.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / biosynthesis
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • Cell Line, Tumor
  • Colorectal Neoplasms / drug therapy
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / pathology
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Down-Regulation
  • Doxorubicin / pharmacology
  • Drug Resistance, Multiple
  • Drug Resistance, Neoplasm
  • Female
  • Fibrosarcoma / drug therapy
  • Fibrosarcoma / genetics
  • Fibrosarcoma / metabolism
  • Fibrosarcoma / pathology
  • Gene Knockdown Techniques
  • Glycoproteins / deficiency
  • Glycoproteins / genetics
  • Glycoproteins / metabolism*
  • Humans
  • Ovarian Neoplasms / drug therapy
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / pathology
  • Phosphorylation
  • Protein Kinase C / metabolism
  • Protein Phosphatase 2 / deficiency
  • Protein Phosphatase 2 / genetics
  • Protein Phosphatase 2 / metabolism*
  • Transfection
  • Vincristine / pharmacology

Substances

  • ABCB1 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Glycoproteins
  • PPP2R3C protein, human
  • tissue-factor-pathway inhibitor 2
  • Vincristine
  • Doxorubicin
  • Cyclic AMP-Dependent Protein Kinases
  • Protein Kinase C
  • Protein Phosphatase 2