Cancer research (Chicago, Ill.), 2018-03, Vol.78 (5), p.1155-1168
2018
Details
- Autor(en) / Beteiligte
- Titel
- Loss of RASSF4 Expression in Multiple Myeloma Promotes RAS-Driven Malignant Progression
- Ist Teil von
- Cancer research (Chicago, Ill.), 2018-03, Vol.78 (5), p.1155-1168
- Ort / Verlag
- United States: American Association for Cancer Research, Inc
- Erscheinungsjahr
- 2018
- Link zum Volltext
- Quelle
- Electronic Journals Library - Freely accessible e-journals
- Beschreibungen/Notizen
- RAS mutations occur frequently in multiple myeloma (MM), but apart from driving progression, they can also stimulate antitumor effects by activating tumor-suppressive RASSF proteins. Although this family of death effector molecules are often silenced in cancers, functional data about RASSF proteins in MM are lacking. Here, we report that is downregulated during MM progression and correlates with a poor prognosis. Promoter methylation analysis in human cell lines revealed an inverse correlation between mRNA levels and methylation status. Epigenetic modulating agents restored expression. Enforced expression of RASSF4 induced G -phase cell-cycle arrest and apoptosis in human cell lines, reduced primary MM cell viability, and blocked MM growth Mechanistic investigations showed that RASSF4 linked RAS to several pro-death pathways, including those regulated by the kinases MST1, JNK, and p38. By activating MST1 and the JNK/c-Jun pathway, RASSF4 sensitized MM cells to bortezomib. Genetic or pharmacological elevation of RASSF4 levels increased the anti-MM effects of the clinical relevant MEK1/2 inhibitor trametinib. Kinome analysis revealed that this effect was mediated by concomitant activation of the JNK/c-Jun pathway along with inactivation of the MEK/ERK and PI3K/mTOR/Akt pathways. Overall, our findings establish RASSF4 as a tumor-suppressive hub in MM and provide a mechanistic rationale for combining trametinib with HDAC inhibitors or bortezomib to treat patients with tumors exhibiting low RASSF4 expression. These findings provide a mechanistic rationale for combining trametinib with HDAC inhibitors or bortezomib in patients with multiple myeloma whose tumors exhibit low RASSF4 expression. .
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0008-5472eISSN: 1538-7445DOI: 10.1158/0008-5472.can-17-1544Titel-ID: cdi_hal_primary_oai_HAL_hal_01864144v1
- Format
- –
- Schlagworte
- 1-Phosphatidylinositol 3-kinase, AKT protein, Animals, Antitumor activity, Apoptosis, Biomarkers, Tumor - genetics, Biomarkers, Tumor - metabolism, Biotechnology, Bortezomib, Bortezomib - pharmacology, c-Jun protein, Cancer, Cell lines, Cell Proliferation, Disease Progression, DNA Methylation, Drug Resistance, Neoplasm, Extracellular signal-regulated kinase, Female, Follow-Up Studies, Gene Expression Regulation, Neoplastic - drug effects, Genetics, Histone deacetylase, Histone Deacetylase Inhibitors - pharmacology, Humans, Inactivation, Inhibitors, Life Sciences, Male, MAP Kinase Signaling System, Methylation, Mice, Mice, Inbred C57BL, Mice, Inbred NOD, Mice, SCID, mRNA, Multiple myeloma, Multiple Myeloma - drug therapy, Multiple Myeloma - genetics, Multiple Myeloma - metabolism, Multiple Myeloma - pathology, Mutation, Prognosis, Promoter Regions, Genetic, Proteins, Proto-Oncogene Proteins c-akt - metabolism, Pyridones - pharmacology, Pyrimidinones - pharmacology, ras Proteins - genetics, Survival Rate, TOR protein, Transcription factors, Tumor Cells, Cultured, Tumor Suppressor Proteins - genetics, Tumor Suppressor Proteins - metabolism, Tumors, Viability, Xenograft Model Antitumor Assays