title: Inhibition of coding region determinant binding protein sensitizes melanoma cells to chemotherapeutic agents.
abstract: We previously reported that malignant melanomas express high levels of the mRNA binding protein coding region determinant binding protein (CRD-BP). This molecule is important for the activation of anti-apoptotic pathways, a mechanism often linked to insensitivity to therapeutics. However, it is not known whether CRD-BP plays a role in the resistance of melanomas to anti-cancer treatment. Here we demonstrate that knockdown of CRD-BP with a specific sh-RNA enhances the effect of dacarbazine, temozolomide, vinblastine, and etoposide on both primary and metastatic melanoma cell lines. CRD-BP down-regulation contributes to cell sensitization by increasing apoptosis and diminishing melanoma cell growth in response to chemotherapeutic agents. Furthermore, inhibition of CRD-BP decreases microphthalmia-associated transcription factor (MITF) expression and reintroduction of MITF partially compensates for the absence of CRD-BP. These findings suggest that high expression of CRD-BP in melanoma cells confers resistance to chemotherapy and that these CRD-BP responses are mediated, at least in part, by MITF.
authors: Department of Dermatology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors: Evisabel A
authors: EA
authors: Craig
authors: Vladimir S
authors: VS
authors: Spiegelman
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005047:Etoposide / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D006801:Humans; D008545:Melanoma / Q000473:pathology*; D051739:Microphthalmia-Associated Transcription Factor / Q000502:physiology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D000077204:Temozolomide; D014747:Vinblastine / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; C406144:IGF2BP1 protein, human; C497234:MITF protein, human; D051739:Microphthalmia-Associated Transcription Factor; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D014747:Vinblastine; D005047:Etoposide; D003606:Dacarbazine; D000077204:Temozolomide