title: Inhibition of p38 MAPK Phosphorylation Is Critical for Bestatin to Enhance ATRA-Induced Cell Differentiation in Acute Promyelocytic Leukemia NB4 Cells.
abstract: Bestatin has been known as an immunomodulating agent in anti-leukemia treatment. The mechanism by which Bestatin enhances all-trans retinoic acid (ATRA)-induced cell differentiation of acute promyelocytic leukemia (APL) cells is generally attributed to inhibition of cell surface CD13/aminopeptidase N activity. Bestatin also exerts its biological activities besides its ability to inhibit aminopeptidase N enzymatic activity. This article provides data to support an alternative mechanism regarding an important role of inhibition of p38 mitogen-activated protein kinase (MAPK) signal pathway in Bestatin's anti-leukemia effect. Bestatin enhanced ATRA-induced differentiation and inhibited ATRA-driven phosphorylation of p38 MAPK in ATRA-sensitive APL NB4 cells. In contrast, Bestatin could not reverse the differentiation block in ATRA-resistant APL MR2 cells, in which ATRA was unable to induce phosphorylation of p38 MAPK. Moreover, CD13 ligation with anti-CD13 antibody WM-15 resulted in phosphorylation of p38 MAPK, reduced the inhibition of Bestatin on the phosphorylation of p38 MAPK, and completely abolished the enhancement of Bestatin on ATRA-inducing differentiation in NB4 cells. This study shows that inhibition of p38 MAPK phosphorylation is critical for Bestatin to enhance ATRA-induced cell differentiation in ATRA-sensitive APL NB4 cells. Results suggested that pharmacological inhibition of the p38 MAPK pathway might enhance ATRA-dependent differentiation.
authors.affiliation: 1Department of Internal Medicine, The Second Division, Anhui Provincial People's Armed Police General Hospital, Hefei, China; and 2Department of Hematology, Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Xijun
authors.initials: X
authors.lastname: Qian
authors.forename: Jingsong
authors.initials: J
authors.lastname: He
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhao
authors.forename: Maofang
authors.initials: M
authors.lastname: Lin
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000378:metabolism*; D018826:CD13 Antigens / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D006801:Humans; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy*; D020935:MAP Kinase Signaling System; D010766:Phosphorylation; D014212:Tretinoin / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D000276:Adjuvants, Immunologic; D000970:Antineoplastic Agents; D014212:Tretinoin; D048051:p38 Mitogen-Activated Protein Kinases; D018826:CD13 Antigens; D007930:Leucine; C012211:ubenimex