The Multidrug Transporter P-Glycoprotein: A Mediator of Melanoma Invasion?

Abstract

Malignant melanoma shows high levels of intrinsic drug resistance associated with a highly invasive phenotype. In this study, we investigated the role of the drug transporter P-glycoprotein (Pgp) in the invasion potential of drug-sensitive (M14 WT, Pgp-negative) and drug-resistant (M14 ADR, Pgp-positive) human melanoma cells. Coimmunoprecipitation experiments assessed the association of Pgp with the adhesion molecule CD44 in multidrug resistant (MDR) melanoma cells, compared with parental ones. In MDR cells, the two proteins colocalized in the plasma membrane as visualized by confocal microscopy and immunoelectron microscopy on ultrathin cryosections. MDR melanoma cells displayed a more invasive phenotype compared with parental cells, as demonstrated by quantitative transwell chamber invasion assay. This was accomplished by a different migration strategy adopted by resistant cells ("chain collective") previously described in tumor cells with high metastatic capacity. The Pgp molecule, after stimulation with specific antibodies, appeared to cooperate with CD44, through the activation of ERK1/2 and p38 mitogen-activated protein kinase (MAPK) proteins. This activation led to an increase of metalloproteinase (MMP-2, MMP-3, and MMP-9) mRNAs, and proteolytic activities, which are associated with an increased invasive behavior. RNA interference experiments further demonstrated Pgp involvement in migration and invasion of resistant melanoma cells. A link was identified between MDR transporter Pgp, and MAPK signaling and invasion.

Hyaluronan, CD44 and Emmprin: Partners in cancer cell chemoresistance

“…The two proteins were found to co-immunoprecipitate, and drugs or siRNA that interfere with the function of P-glycoprotein were shown to inhibit cell motility and invasion (MilettiGonzalez et al, 2005), which are properties strongly related to CD44 receptor activity (Hill et al, 2006b;Tzircotis et al, 2005). In a similar way, co-immunoprecipitation and co-localization of P-glycoprotein and CD44 have been demonstrated in drug resistant melanoma cells, and the two molecules were found to cooperate in promoting invasive behavior (Colone et al, 2008). Moreover, ABC transporter inhibitors have been shown to interfere with hyaluronan secretion in fibroblasts (Prehm and Schumacher, 2004).…”

“…In addition to its pro-malignant and anti-apoptotic activities, this pathway may lead to increased expression of ABC family multidrug transporters, such as P-glycoprotein (MDR1/ABCB1), multi-drug resistance-associated protein-1 (MRP-1/ABCC1) and breast cancer resistance protein (BCRP/ABCG2) (Lee et al, 2004;Misra et al, 2005;Mogi et al, 2003). Not surprisingly, several publications have demonstrated a close relationship between malignant cell properties and resistance to therapy; major factors that appear to mediate this relationship are CD44 and emmprin (Colone et al, 2008;Miletti-Gonzalez et al, 2005;Raguz et al, 2004;Yang et al, 2003).…”

Identification of a ZEB2-MITF-ZEB1 transcriptional network that controls melanogenesis and melanoma progression

“…16,17 Drug resistance of malignant melanoma cells has been associated with the expression of the drug transporter P-glycoprotein (PGP) and increased migratory and invasive behavior. 18 EMT (Epithelialto-mesenchymal transition) has a key role in the collective movement of normal cells during different stages of embryonic development, whereas in adults it has been associated with several pathologies, including fibrosis and cancer progression. 19,20 EMT is a process in which epithelial cells lose their epithelial characteristics, gain mesenchymal features and become migratory.…”

Characterization of SLC transporters in human skin

“…In addition, these transporters also play a role in the active efflux of contact allergens and endogenous compounds such as steroid hormones from normal human epidermal keratinocytes (NHEK) [13]. Further studies demonstrated P-gp involvement in migration and invasion of resistant melanoma cells [14], whereas very low or no expression of P-gp was detected in primary human melanocytes [15]. Recently the expression pattern of human ATP-binding cassette transporters was reported in human skin [16].…”