Cis-vaccenic acid induces differentiation and up-regulates gamma globin synthesis in K562, JK1 and transgenic mice erythroid progenitor stem cells

• Published in: European journal of pharmacology 2016-04, Vol.776, p.9-18
• Main Authors: Aimola, Idowu A., Inuwa, Hajiya M., Nok, Andrew J., Mamman, Aisha I., Bieker, James J.
• Format: Article
• Language: English
• Subjects: Acetyltransferases - antagonists & inhibitors; Animals; Cell Differentiation - drug effects; Cis-vaccenic acid; Erythroid Precursor Cells - cytology; Erythroid Precursor Cells - drug effects; Erythroid Precursor Cells - metabolism; Erythroid progenitor stem cells; Erythropoietin - pharmacology; Fetal hemoglobin; Fetus - metabolism; Gamma globin; gamma-Globins - biosynthesis; gamma-Globins - genetics; gamma-Globins - metabolism; Hemoglobins - metabolism; Humans; K562 Cells; Kruppel-Like Transcription Factors - genetics; Mice; Mice, Transgenic; Mono-unsaturated fatty acid; Oleic Acids - pharmacology; Phenylthiourea - analogs & derivatives; Phenylthiourea - pharmacology; RNA, Messenger - genetics; RNA, Messenger - metabolism; Sickle cell anemia; Stearoyl-CoA Desaturase - antagonists & inhibitors; Thiocarbamates - pharmacology; Up-Regulation - drug effects
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2016.02.041

Gamma globin induction remains a promising pharmacological therapeutic treatment mode for sickle cell anemia and beta thalassemia, however Hydroxyurea remains the only FDA approved drug which works via this mechanism. In this regard, we assayed the γ-globin inducing capacity of Cis-vaccenic acid (CVA). CVA induced differentiation of K562, JK1 and transgenic mice primary bone marrow hematopoietic progenitor stem cells. CVA also significantly up-regulated γ-globin gene expression in JK-1 and transgenic mice bone marrow erythroid progenitor stem cells (TMbmEPSCs) but not K562 cells without altering cell viability. Increased γ-globin expression was accompanied by KLF1 suppression in CVA induced JK-1 cells. Erythropoietin induced differentiation of JK-1 cells 24h before CVA induction did not significantly alter CVA induced differentiation and γ-globin expression in JK-1 cells. Inhibition of JK-1 and Transgenic mice bone marrow erythroid progenitor stem cells Fatty acid elongase 5 (Elovl5) and Δ9 desaturase suppressed the γ-globin inductive effects of CVA. CVA treatment failed to rescue γ-globin expression in Elovl5 and Δ9-desaturase inhibited cells 48h post inhibition in JK-1 cells. The data suggests that CVA directly modulates differentiation of JK-1 and TMbmEPSCs, and indirectly modulates γ-globin gene expression in these cells. Our findings provide important clues for further evaluations of CVA as a potential fetal hemoglobin therapeutic inducer