Inhibition of Cot1/Tlp2 oncogene in AML cells reduces ERK5 activation and upregulates p27Kip1 concomitant with enhancement of differentiation and cell cycle arrest induced by silibinin and 1,25-dihydroxyvitamin D 3

Xuening Wang, Elzbieta Gocek, Victoria Novik, Jonathan S. Harrison, Michael Danilenko, George P. Studzinski

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    43 Scopus citations

    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 D 3 (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, overexpression 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 p27Kip1, 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.

    Original languageEnglish
    Pages (from-to)4542-4551
    Number of pages10
    JournalCell Cycle
    Volume9
    Issue number22
    DOIs
    StatePublished - 15 Nov 2010

    Keywords

    • Cot1 oncogene
    • ERK5
    • MAPK signaling
    • Plant antioxidants
    • Silibinin
    • Vitamin D

    ASJC Scopus subject areas

    • Molecular Biology
    • Developmental Biology
    • Cell Biology

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