RAF-1/MEK/ERK pathway regulates ATRA-induced differentiation in acute promyelocytic leukemia cells through C/EBPβ, C/EBPε and PU.1

• Published in: Leukemia research 2016-06, Vol.45, p.68-74
• Main Authors: Weng, Xiang-qin, Sheng, Yan, Ge, Dong-zheng, Wu, Jing, Shi, Lei, Cai, Xun
• Format: Article
• Language: English
• Subjects: Acute promyelocytic leukemia; All-trans retinoic acid; Antineoplastic Agents - pharmacology; CCAAT-Enhancer-Binding Protein-beta - biosynthesis; CCAAT-Enhancer-Binding Protein-beta - drug effects; CCAAT-Enhancer-Binding Proteins - biosynthesis; CCAAT-Enhancer-Binding Proteins - drug effects; Cell Differentiation - drug effects; Cell Line, Tumor; Differentiation; Granulocytes - drug effects; Granulocytes - pathology; Hematology, Oncology and Palliative Medicine; Humans; Leukemia, Promyelocytic, Acute - drug therapy; Leukemia, Promyelocytic, Acute - metabolism; Leukemia, Promyelocytic, Acute - pathology; MAP Kinase Signaling System - physiology; MEK; Proto-Oncogene Proteins - biosynthesis; Proto-Oncogene Proteins - drug effects; Proto-Oncogene Proteins c-raf - physiology; Trans-Activators - biosynthesis; Trans-Activators - drug effects; Tretinoin - pharmacology
• ISSN: 0145-2126; 1873-5835
• DOI: 10.1016/j.leukres.2016.03.008

Abstract MEK/ERK signal pathway was required for the differentiation of granulocytes, megakaryocytes and erythrocytes. Recently, MEK/ERK cascade was reported to be involved in all-trans retinoic acid (ATRA) induced differentiation in acute promyelocytic leukemia (APL) cells. However, the upstream and downstream molecules of MEK/ERK signal pathway in this cell model remains to be elucidated. In this work, we showed that RAF-1 was activated and the blockade of RAF-1 activation attenuated MEK/ERK activation as well as ATRA-induced differentiation. ATRA-enhanced protein levels of C/EBPβ, C/EBPε and PU.1, which were required for differentiation in APL cells, were suppressed by the specific inhibitor of MEK. However, MEK inhibition had no effect on the degradation of PML-RARα fusion protein or the restoration of PML nuclear bodies by ATRA treatment. Taken together, our study suggested that RAF-1/MEK/ERK cascade was involved in ATRA-induced differentiation in APL cells through enhancing the protein level of C/EBPβ, C/EBPε and PU.1.