RalA, a GTPase targeted by miR‑181a, promotes transformation and progression by activating the Ras‑related signaling pathway in chronic myelogenous leukemia
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Chunming Gu1,2,*, Maoxiao Feng1,*, Zhao Yin1,*, Xiaochuang Luo1, Juhua Yang1, Yumin Li1, Tianfu Li3, Ruirui Wang3, Jia Fei1,2
1Department of Biochemistry and Molecular Biology, Medical College of Jinan University, Guangzhou 510632, China
2Insititute of Chinese Integrative Medicine, Medical College of Jinan University, Guangzhou 510632, China
3Department of Clinical Medicine, Medical College of Jinan University, Guangzhou 510632, China
*These authors have contributed equally to this work
Jia Fei, e-mail: [email protected]
Keywords: RalA GTPases, chronic myelogenous leukemia, malignant transformation, imatinib, Ras signaling pathway
Received: September 04, 2015 Accepted: February 16, 2016 Published: March 08, 2016
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.
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