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

• Verfasst von: Liedert, Bernd [VerfasserIn]
• Verfasst von: Schadendorf, Dirk [VerfasserIn]
• Titel: Overexpression of cMOAT (MRP2/ABCC2) is associated with decreased formation of platinum-DNA adducts and decreased G2-arrest in melanoma cells resistant to cisplatin
• Verf.angabe: Bernd Liedert, Verena Materna, Dirk Schadendorf, Jürgen Thomale, Hermann Lage
• E-Jahr: 2015
• Jahr: 8 December 2015
• Jahr des Originals: 2003
• Umfang: 5 S.
• Fussnoten: Elektronische Reproduktion der Druckausgabe ; Im Titel ist die Zahl 2 im Ausdruck "G2-arrest" tiefgestellt ; Gesehen am 23.11.2020
• Titel Quelle: Enthalten in: The journal of investigative dermatology
• Ort Quelle: Amsterdam : Elsevier, 1938
• Jahr Quelle: 2003
• Band/Heft Quelle: 121(2003), 1, Seite 172-176
• ISSN Quelle: 1523-1747
• DOI: doi:10.1046/j.1523-1747.2003.12313.x
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: ABCC2
• Sach-SW: cisplatin
• Sach-SW: cMOAT
• Sach-SW: drug resistance
• Sach-SW: melanoma
• Sach-SW: MeWo
• Sach-SW: MRP2
• K10plus-PPN: 1740400658

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. Cisplatinresistant 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.