Overexpression of cMOAT (MRP2/ABCC2) is associated with decreased formation of platinum-DNA adducts and decreased G2-arrest in melanoma cells resistant to cisplatin

J Invest Dermatol. 2003 Jul;121(1):172-6. doi: 10.1046/j.1523-1747.2003.12313.x.

Abstract

Resistance to various anti-neoplastic agents is a common observation in clinical management of melanoma. The biologic mechanisms conferring these different drug-resistant phenotypes, including resistance against the commonly used anti-cancer drug cisplatin, are unclear. In order to elucidate the role of the membrane adenosine triphosphate binding cassette-transporter cMOAT (canalicular multispecific anion transporter) (MRP2/ABCC2) in cisplatin resistance of melanoma, the expression of this protein was analyzed in the platinum drug-resistant cell line MeWo CIS 1. Cisplatin-resistant melanoma cells showed a distinct overexpression of cMOAT on mRNA and protein level. This observation was accompanied by a reduced formation of platinum-induced intrastrand cross-links in the nuclear DNA measured by an immunocytologic assay. This decrease in DNA platination was accompanied by an accelerated re-entry into the cell cycle after the typical cisplatin-induced G2 arrest, and a resistance to undergo apoptosis. Kinetics of formation and elimination of platinum-DNA adducts suggest that the DNA repair capacity for Pt-d(GpG) adducts was not elevated in platinum drug-resistant melanoma cells. The decrease in platinum-DNA adduct formation in cisplatin-resistant melanoma cells was rather a reflection of the protecting activity of the transporter cMOAT. In conclusion, the functional inhibition of cMOAT might be a promising strategy in the reversal of resistance to platinum-based anti-cancer drugs in human melanoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology*
  • Cisplatin / metabolism
  • Cisplatin / pharmacology*
  • DNA Adducts / metabolism*
  • Drug Resistance, Neoplasm
  • G2 Phase / drug effects
  • G2 Phase / genetics
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Melanoma*
  • Membrane Transport Proteins*
  • Multidrug Resistance-Associated Proteins / genetics*
  • Phenotype
  • Platinum / metabolism
  • Platinum / pharmacology
  • Skin Neoplasms*
  • Transfection
  • Tumor Cells, Cultured / cytology
  • Tumor Cells, Cultured / drug effects

Substances

  • Antineoplastic Agents
  • DNA Adducts
  • Membrane Transport Proteins
  • Multidrug Resistance-Associated Proteins
  • Platinum
  • multidrug resistance-associated protein 2
  • Cisplatin