title: Inhibition of Cot1/Tlp2 oncogene in AML cells reduces ERK5 activation and up-regulates p27Kip1 concomitant with enhancement of differentiation and cell cycle arrest induced by silibinin and 1,25-dihydroxyvitamin D(3).
abstract: Acute myelogenous leukemia (AML) is a disease characterized by dysregulated cell proliferation associated with impaired cell differentiation, and current treatment regimens rarely save the patient. Thus, new mechanism-based approaches are needed to improve prognosis of this disease. We have investigated in preclinical studies the potential anti-leukemia use of the plant-derived polyphenol Silibinin (SIL) in combination with 1,25-dihydroxyvitamin D3 (1,25D). Although most of the leukemic blasts ex vivo responded by differentiation to treatment with this combination, the reasons for the absence of SIL-1,25D synergy in some cases were unclear. Here we report that failure of SIL to enhance the action of 1,25D is likely due to the SIL-induced increase in the activity of differentiation-antagonizing cell components, such as ERK5. This kinase is under the control of Cot1/Tlp2, and inhibition of Cot1 activity by a specific pharmacological inhibitor 4-(3-chloro-4-fluorophenylamino)-6-(pyridin-3-yl-methylamino-3-cyano-[1-7]-naphthyridine, or by Cot1 siRNA, increases the differentiation by SIL/1,25D combinations. Conversely, over-expression of a Cot1 construct increases the cellular levels of P-ERK5, and SIL/1,25D-induced differentiation and cell cycle arrest are diminished. It appears that reduction in ERK5 activity by inhibition of Cot1 allows SIL to augment the expression of 1,25D-induced differentiation promoting factors and cell cycle regulators such as p27 (Kip1) , which leads to cell cycle arrest. This study shows that in some cell contexts SIL/1,25D can promote expression of both differentiation-promoting and differentiation-inhibiting genes, and that the latter can be neutralized by a highly specific pharmacological inhibitor, suggesting a potential for supplementing treatment of AML with this combination of agents.
authors.affiliation: Department of Pathology and Laboratory Medicine, New Jersey Medical School, University of Medicine and Dentistry New Jersey, Newark, USA.
authors.forename: Xuening
authors.initials: X
authors.lastname: Wang
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Gocek
authors.forename: Victoria
authors.initials: V
authors.lastname: Novik
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Harrison
authors.forename: Michael
authors.initials: M
authors.lastname: Danilenko
authors.forename: George P
authors.initials: GP
authors.lastname: Studzinski
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D016193:G1 Phase; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D048054:Mitogen-Activated Protein Kinase 7 / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D000077385:Silybin; D012838:Silymarin / Q000627:therapeutic use*; D015854:Up-Regulation; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D012838:Silymarin; D014807:Vitamin D; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000077385:Silybin; C097949:1,25-dihydroxyvitamin D; D048054:Mitogen-Activated Protein Kinase 7; D020930:MAP Kinase Kinase Kinases; C069937:MAP3K8 protein, human