TY - JOUR
T1 - The role of eIF4E in response and acquired resistance to vemurafenib in melanoma
AU - Zhan, Yao
AU - Dahabieh, Michael S
AU - Rajakumar, Arjuna
AU - Dobocan, Monica C
AU - M'Boutchou, Marie-Noël
AU - Goncalves, Christophe
AU - Lucy, Shiru L
AU - Pettersson, Filippa
AU - Topisirovic, Ivan
AU - van Kempen, Léon
AU - Del Rincón, Sonia V
AU - Miller, Wilson H
PY - 2015
Y1 - 2015
N2 - In eukaryotic cells, the rate-limiting component for cap-dependent mRNA translation is the translation initiation factor eIF4E. eIF4E is overexpressed in a variety of human malignancies, but whether it has a role in melanoma remains obscure. We hypothesized that eIF4E promotes melanoma cell proliferation and facilitates the development of acquired resistance to the BRAF inhibitor vemurafenib. We show that eIF4E is overexpressed in a panel of melanoma cell lines, compared with immortalized melanocytes. Knockdown of eIF4E significantly repressed the proliferation of a subset of melanoma cell lines. Moreover, in BRAF(V600E) melanoma cell lines, vemurafenib inhibits 4E-BP1 phosphorylation, thus promoting its binding to eIF4E. Cap-binding and polysome profiling analysis confirmed that vemurafenib stabilizes the eIF4E-4E-BP1 association and blocks mRNA translation, respectively. Conversely, in cells with acquired resistance to vemurafenib, there is an increased dependence on eIF4E for survival; 4E-BP1 is highly phosphorylated and thus eIF4E-4E-BP1 associations are impeded. Moreover, increasing eIF4E activity by silencing 4E-BP1/2 renders vemurafenib-responsive cells more resistant to BRAF inhibition. In conclusion, these data suggest that therapeutically targeting eIF4E may be a viable means of inhibiting melanoma cell proliferation and overcoming vemurafenib resistance.
AB - In eukaryotic cells, the rate-limiting component for cap-dependent mRNA translation is the translation initiation factor eIF4E. eIF4E is overexpressed in a variety of human malignancies, but whether it has a role in melanoma remains obscure. We hypothesized that eIF4E promotes melanoma cell proliferation and facilitates the development of acquired resistance to the BRAF inhibitor vemurafenib. We show that eIF4E is overexpressed in a panel of melanoma cell lines, compared with immortalized melanocytes. Knockdown of eIF4E significantly repressed the proliferation of a subset of melanoma cell lines. Moreover, in BRAF(V600E) melanoma cell lines, vemurafenib inhibits 4E-BP1 phosphorylation, thus promoting its binding to eIF4E. Cap-binding and polysome profiling analysis confirmed that vemurafenib stabilizes the eIF4E-4E-BP1 association and blocks mRNA translation, respectively. Conversely, in cells with acquired resistance to vemurafenib, there is an increased dependence on eIF4E for survival; 4E-BP1 is highly phosphorylated and thus eIF4E-4E-BP1 associations are impeded. Moreover, increasing eIF4E activity by silencing 4E-BP1/2 renders vemurafenib-responsive cells more resistant to BRAF inhibition. In conclusion, these data suggest that therapeutically targeting eIF4E may be a viable means of inhibiting melanoma cell proliferation and overcoming vemurafenib resistance.
KW - Adaptor Proteins, Signal Transducing/metabolism
KW - Cell Line, Tumor
KW - Cell Proliferation/drug effects
KW - Drug Resistance, Neoplasm/drug effects
KW - Eukaryotic Initiation Factor-4E/drug effects
KW - Gene Knockdown Techniques
KW - Gene Silencing
KW - Humans
KW - Indoles/pharmacology
KW - Melanoma/pathology
KW - Phosphoproteins/metabolism
KW - Phosphorylation
KW - Proto-Oncogene Proteins B-raf
KW - RNA, Small Interfering/pharmacology
KW - Skin Neoplasms/pathology
KW - Sulfonamides/pharmacology
KW - Vemurafenib
U2 - 10.1038/jid.2015.11
DO - 10.1038/jid.2015.11
M3 - Article
C2 - 25615552
SN - 0022-202X
VL - 135
SP - 1368
EP - 1376
JO - Journal of Investigative Dermatology
JF - Journal of Investigative Dermatology
IS - 5
ER -