RalA, a GTPase targeted by miR-181a, promotes transformation and progression by activating the Ras-related signaling pathway in chronic myelogenous leukemia
| Autor: | Zhao Yin, Xiaochuang Luo, Maoxiao Feng, Juhua Yang, Yumin Li, Li Tianfu, Chunming Gu, Jia Fei, Wang Ruirui |
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| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
malignant transformation Fusion Proteins bcr-abl Mice Nude Apoptosis 03 medical and health sciences Mice 0302 clinical medicine Cell Movement hemic and lymphatic diseases Leukemia Myelogenous Chronic BCR-ABL Positive Ras signaling pathway Biomarkers Tumor Tumor Cells Cultured Medicine Animals Humans Small GTPase RalA GTPases Cell Proliferation Mice Inbred BALB C ABL Kinase business.industry Xenograft Model Antitumor Assays RALA MicroRNAs chronic myelogenous leukemia 030104 developmental biology Cell Transformation Neoplastic Oncology Ras Signaling Pathway Ral GTP-Binding Proteins imatinib Drug Resistance Neoplasm 030220 oncology & carcinogenesis Immunology Cancer research Disease Progression ras Proteins ral GTP-Binding Proteins Signal transduction business K562 cells Signal Transduction Research Paper |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | BCR/ABL is a well-known activator of multiple signaling pathways. RalA, a Ras downstream signaling molecule and a small GTPase, plays an important role in Bcr-Abl-induced leukemogenesis but the exact mechanism remains elusive. Here, we show that RalA GTPase activity is commonly high in chronic myelogenous leukemia (CML) cell lines and patient samples. Overexpression of RalA results in malignant transformation and progression, and induces resistance to imatinib (IM) in BaF3 and K562 cell lines. RalA reduced survival and led to IM resistance in a xenografted mouse model. Ablation of RalA by either siRNA or miR-181a, a RalA targeting microRNA, attenuated the malignant phenotypes in K562 cells. RBC8, a selective Ral inhibitor, enhanced the inhibitory effects of IM in K562, KCL22 and BaF3-P210 cells. Interestingly, the phospho-specific protein microarray assay revealed that multiple phosphorylation signal proteins were decreased by RalA inhibition, including SAPK, JNK, SRC, VEGFR2, P38 MAPK, c-Kit, JunB, and Keratin18. Among them, P38 MAPK and SAPK/JNK are Ras downstream signaling kinases. Taken together, RalA GTPase might be an important oncogene activating the Ras-related signaling pathway in CML. |
| Databáze: | OpenAIRE |
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