Association of MITF and other melanosome-related proteins with chemoresistance in melanoma tumors and cell lines.
Previous studies in cell lines have suggested a role for melanosomes and related protein trafficking pathways in melanoma drug response. We have investigated the expression of six proteins related to melanosomes and melanogenesis (MITF, GPR143, gp100/PMEL, MLANA, TYRP1, and RAB27A) in pretreatment metastases from melanoma patients (n = 52) with different response to dacarbazine/temozolomide. Microphthalmia-associated transcription factor (MITF) and G-protein coupled receptor 143 (GPR143) showed significantly higher expression in nonresponders compared with responders. The premelanosome protein (gp100/PMEL) has been indicated previously in resistance to cisplatin in melanoma cells, but the expression levels of gp100/PMEL showed no association with response to dacarbazine/temozolomide in our clinical material. We also investigated the effects on chemosensitivity of siRNA inhibition of gp100/PMEL in the MNT-1 melanoma cell line. As expected from the study of the tumor material, no effect was detected with respect to response to temozolomide. However, knockdown of gp100/PMEL sensitized the cells to both paclitaxel and cisplatin. Overall, our results suggest that MITF, and several MITF-regulated factors, are associated with resistance to chemotherapy in melanoma and that different MITF targets can be of importance for different drugs.
Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. carolina.johansson@ki.se
Carolina
C
Hertzman Johansson
Alireza
A
Azimi
Marianne
M
Frostvik Stolt
Seyedmehdi
S
Shojaee
Henning
H
Wiberg
Eva
E
Grafström
Johan
J
Hansson
Suzanne
S
Egyházi Brage
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020460:Melanosomes / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D034622:RNA Interference; D012878:Skin Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014158:Transcription, Genetic; D014162:Transfection; D016896:Treatment Outcome; D058951:gp100 Melanoma Antigen / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D005136:Eye Proteins; C095276:GPR143 protein, human; C497234:MITF protein, human; D008562:Membrane Glycoproteins; D051739:Microphthalmia-Associated Transcription Factor; C548637:PMEL protein, human; D058951:gp100 Melanoma Antigen