Bryostatin 1 (bryo1)-induced monocytic differentiation in THP-1 human leukemia cells is associated with enhanced c-fyn tyrosine kinase and M-CSF receptors.
Bryostatin 1 (bryo1), a naturally occurring macrocyclic lactone derived from the marine bryozoan Bugula neritina is a potent protein kinase C (PKC) activator. In this report, we investigated the role of c-fyn protein, a src-related protein tyrosine kinase (PTK), during bryo1-induced monocytic differentiation in a human leukemia cell line, THP-1. Bryo1 treatment for 24 h inhibited the proliferation of THP-1 cells and caused a major fraction of them to become adherent cells with distinct monocyte/macrophage features and enhanced expression of M-CSF receptors (M-CSFR), a hallmark of mature macrophages. The THP-1 cells in control cultures expressed low but detectable levels of c-fyn proteins. Treatment of THP-1 cells with bryo1 resulted in an enhanced expression of c-fyn proteins, but not c-lyn proteins, another member of the src-family of kinases. The bryo1 treatment also enhanced the levels of both c-fyn tyrosine kinase and autophosphorylation activities in THP-1 cells. Using a combined immunoprecipitation and immunoblot analysis, bryo1 was shown to promote an enhanced association between c-fyn kinase and M-CSFR. The inducing activity of bryo1 was associated with PKC activation; treatment of THP-1 cells with bryo1 led to a rapid and transient elevation of total PKC activity in THP-1 cells. These results show that enhanced expression and activation of fyn kinases are critical events associated with monocytic differentiation induced by bryo1 in THP-1 cells. Our findings may be of clinical relevance, as bryo1 has been used in clinical trials of cancer patients.
Li
Y
Y
Department of Internal Medicine, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Mohammad
R M
RM
al-Katib
A
A
Varterasian
M L
ML
Chen
B
B
D000970:Antineoplastic Agents / Q000494:pharmacology*; D015415:Biomarkers; D054713:Bryostatins; D002454:Cell Differentiation / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D004789:Enzyme Activation; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D007783:Lactones / Q000494:pharmacology*; D007948:Leukemia, Monocytic, Acute; D018942:Macrolides; D008264:Macrophages / Q000166:cytology; D009000:Monocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D011493:Protein Kinase C / Q000096:biosynthesis; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D051076:Proto-Oncogene Proteins c-fyn; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000096:biosynthesis*; D011994:Recombinant Proteins / Q000096:biosynthesis; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D000970:Antineoplastic Agents; D015415:Biomarkers; D054713:Bryostatins; D007783:Lactones; D018942:Macrolides; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; C046785:bryostatin 1; D011505:Protein-Tyrosine Kinases; D016186:Receptor, Macrophage Colony-Stimulating Factor; C494957:FYN protein, human; D051076:Proto-Oncogene Proteins c-fyn; D011493:Protein Kinase C