Untersuchung der Genexpression von ABC- und SLC-Transmembranproteinen mit Beteiligung am aktiven Transport von Antigenen, Eikosanoiden und Zytostatika beim malignen Melanom

摘要

Malignant melanoma is the most aggressive form of human skin cancer. Rising incidence in the Caucasian population and disappointing results of chemotherapy at metastatic stage make melanoma a major medical challenge. The last decades have shown great progress in discovery and description of transporters that confer drug resistance or mediate inflammatory tumour response like the multidrug resistance-associated proteins (MRP), the organic anion transporting polypeptides (OATP) and transporters associated with antigen processing (TAP). It is presumed that influx transport proteins such as OATP (uptake, phase 0) interact synergistically with metabolizing enzymes such as CYP (biotransformation, phase I and II) and effluxers like MRP (anti-transport, phase III). Meanwhile, it has become clear that the MRP/OATP combination is involved in the transport not only of endo- or xenobiotics, but also of lipid mediators like prostaglandins and leukotrienes. Some MRPs and OATPs show similarities in substrate profiles and function. Coexpression in melanoma is not well known yet, but evidence suggests a coordinate activity of MRP and OATP in vectorial transmembranous substrate transfer. Little is known about the pattern of transporters in malignant melanoma. In this study, the differential mRNA expression of 18 cell lines originating from primary melanoma and metastases of malignant melanoma compared with normal human melanocytes was examined with Affymetrix microarray and consecutively confirmed by real-time PCR. High basic expression levels were detected for MRP1, MRP2, MRP4, OATP3A1 and the still functionally uncharacterized OATP5A1. We could also show a down-regulation of TAP1. TAP1 mediates antigen presentation via MHC-I. MRP can confer drug resistance by decreasing the intracellular drug concentration. One example is cisplatin resistance due to MRP2. Eicosanoid-transport is mediated by MRP4 (e.g. PGE2, LTB4), MRP1 (LTC4) and OATP3A1 (PGE2). There is growing evidence that these lipids play a key role in cell proliferation and migration. Showing the mRNA expression of efflux and influx transporters, we provide data that strongly support the functional role of MRP and OATP in drug resistance and inflammation in malignant melanoma.