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KSRP modulates melanoma growth and efficacy of vemurafenib.

ABSTRACT: The majority of melanomas carry an oncogenic BRAF mutation (BRAF^V600E), which results in constitutive kinase activity driving melanoma proliferation. While inhibitors of BRAF^V600E (BRAFi) effectively lead to rapid tumor shrinkage, most patients treated with BRAFi develop acquired resistance. Identification of factors as regulators of melanoma growth and as potential sources of resistance is thus crucial for the design of improved therapies to treat advanced melanoma with more durable responses. Here, we show that KH-type splicing regulatory protein (KSRP) is critical for proliferation of melanoma cells without and with acquired resistance to vemurafenib. Silencing KSRP reduces cell proliferation and augments the growth suppressive effects of vemurafenib. We identify killin (KLLN), a p53-regulated DNA replication inhibitor, as a downstream effector of growth inhibition by KSRP silencing and demonstrate that KSRP promotes decay of KLLN mRNA through an RNA-protein interaction. Using heterologous mRNA reporters, we show that a U-rich element within the 3' untranslated region of KLLN is responsible for KSRP-dependent mRNA decay. These findings implicate that KSRP is an important regulator of melanoma cell growth in part through controlling KLLN mRNA stability.

SUBMITTER: Liu W

PROVIDER: S-EPMC7446395 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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KSRP modulates melanoma growth and efficacy of vemurafenib.

Liu Wenwen W Chou Chu-Fang CF Liu Shanrun S Crossman David D Yusuf Nabiha N Wu Yunkun Y Chen Ching-Yi CY

Biochimica et biophysica acta. Gene regulatory mechanisms 20190630 8

The majority of melanomas carry an oncogenic BRAF mutation (BRAF<sup>V600E</sup>), which results in constitutive kinase activity driving melanoma proliferation. While inhibitors of BRAF<sup>V600E</sup> (BRAFi) effectively lead to rapid tumor shrinkage, most patients treated with BRAFi develop acquired resistance. Identification of factors as regulators of melanoma growth and as potential sources of resistance is thus crucial for the design of improved therapies to treat advanced melanoma with mo ...[more]

PMID: 31269460

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Project description:Background:Despite the progress made in the clinical management of metastatic melanoma, a patient's response to treatment cannot be fully predicted, and intrinsic or acquired resistance that is developed in most melanoma patients warrants further research efforts. In addition to genetic factors, microenvironmental input should be considered to explain the diversity of response to treatment among melanoma patients. In this study, we evaluated the impact of insulin on patient-derived BRAFV600E melanoma cells, either untreated or treated with vemurafenib or trametinib, inhibitors of BRAFV600 and MEK1/2, respectively. Methods:Cells were cultured in serum-free conditions, either with or without insulin. The activity of the MAPK/ERK and PI3K/AKT pathways was assessed by Western blotting, cell viability, and percentages of Ki-67- and NGFR-positive cells by flow cytometry. Transcript levels were analyzed using qRT-PCR, and ?-H2AX levels by immunoblotting and confocal microscopy. A luminescence-based assay was used to measure glutathione content. Results:While insulin did not influence the MAPK/ERK pathway activity, it had a strong influence on melanoma cells, in which this pathway was suppressed by either vemurafenib or trametinib. In the presence of insulin, both drugs were much less efficient in 1) inhibiting proliferation and reducing the percentage of Ki-67-positive cells, and 2) inducing apoptosis and phosphorylation of histone H2AX in melanoma cells. Changes induced by vemurafenib and trametinib in glutathione homeostasis and DNA repair gene expression were also attenuated by insulin. Moreover, insulin impaired the combined effects of targeted drugs and doxorubicin in melanoma cells. In addition to insulin-induced PI3K/AKT activity, which was either transient or sustainable depending on the cell line, an insulin-triggered increase in the percentage of cells expressing NGFR, a marker of neural crest stem-like cells, may contribute to the reduced drug efficacy. Conclusion:Our results demonstrate the role of insulin in reducing the efficacy of vemurafenib and trametinib. This needs clinical assessment.

Dataset Information

KSRP modulates melanoma growth and efficacy of vemurafenib.

Publications

KSRP modulates melanoma growth and efficacy of vemurafenib.

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