Activation of the MEK/MAPK Pathway Is Involved in Bryostatin1-Induced Monocytic Differenciation and Up-regulation of X-Linked Inhibitor of Apoptosis Protein

• Published in: Experimental cell research 2002-01, Vol.272 (2), p.192-198
• Main Authors: Lin, Hong, Chen, Catheryne, Li, Xiaohua, Chen, Ben D.
• Format: Article
• Language: English
• Subjects: Apoptosis; bryostatin; Bryostatins; Cell Differentiation; differentiation; DNA-Binding Proteins; Enzyme Activation; Enzyme Inhibitors - metabolism; Gene Expression; Humans; I-kappa B Proteins; Lactones - pharmacology; leukemia; Macrolides; MAP Kinase Signaling System - physiology; MEK; Mitogen-Activated Protein Kinase Kinases - metabolism; Mitogen-Activated Protein Kinases - metabolism; Monocytes - cytology; Monocytes - metabolism; NF-kappa B - metabolism; NF-KappaB Inhibitor alpha; NF-κB; Protein Biosynthesis; Protein-Serine-Threonine Kinases; Proteins - genetics; Proteins - metabolism; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; Tumor Cells, Cultured; Up-Regulation; X-Linked Inhibitor of Apoptosis Protein; XIAP
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1006/excr.2001.5417

Induction of monocytic differentiation by bryostatin1 (bryo1) conferred on THP-1 leukemia cells the ability to resist Z-LLL-CHO-induced apoptosis. The mechanism of resistance developed during this process was investigated. Apoptosis resistance was associated with an enhanced expression of X-linked inhibitor of apoptosis protein (XIAP), an endogenous caspase inhibitor, in differentiated THP-1 cells. Bryo1 also increased the level of c-IAP-1, yet decreased the level of c-IAP-2 in THP-1 cells, indicating that distinct regulatory mechanisms are operative. In addition, treatment of THP-1 cells with bryo1 induced a rapid and sustained activation of MEK, prior to the upregulation of XIAP and monocytic differentiation. Pretreatment of THP-1 cells with MEK inhibitors (U0126 and PD98059) prior to bryo1 induction blocked the expression of both XIAP and the c-fms product (M-CSF receptor), a hallmark of monocytic differentiation, but not Bcl-2. In addition, the expression of XIAP in bryo1-treated cells was inhibited by CAPE, a NF-κB-specific inhibitor, indicating that its expression is under the transcriptional regulation of NF-κB downstream of the MEK/MAPK pathway. The importance of XIAP in mediating apoptosis resistance was illustrated in cells transiently transfected with XIAP, which conferred on THP-1 cells the ability to resist Z-LLL-CHO-induced apoptosis. These findings suggest that the expression of XIAP is linked to monocytic differentiation in bryo1-treated THP-1 cells and represents one of the potential antiapoptotic mechanisms acquired during this process.