Vitamin D derivatives, including its physiological form 1α,25(
OH)2
vitamin D3 (1,25D), have anti-
tumor actions demonstrated in cell culture and confirmatory epidemiological associations are frequently reported. However, their promise for use in the
cancer clinic is still incompletely fulfilled, suggesting that a better understanding of the molecular events initiated by these compounds is needed for therapeutic advances. While ERK1/2 has been intensely investigated and is known to transmit signals for cell survival, growth, and differentiation, the role of other MAPK pathways has been studied sporadically. Therefore, we utilized
acute myeloid leukemia (AML) cells in culture (HL60 and U937), to determine if ERK5 has a role in 1,25D-induced terminal differentiation which is distinct from the previously shown involvement of ERK1/2. We previously found that inhibition of
kinase activity of ERK5 by specific pharmacological inhibitors
BIX02189 or
XMD8-92 results in higher expression of general myeloid marker CD11b, but a lower expression of the monocytic marker CD14. In contrast, the inhibition of the ERK1/2 pathway by
PD98059 or
U0126 reduced the expression of all
differentiation markers studied. We report here for the first time that the differentiation changes induced by ERK5 inhibitors are accompanied by the inhibition of cell proliferation, and this occurs in the both G1 and G2 phases of the cell cycle. Of note, inhibition of ERK5 auto-phosphorylation by
XMD8-92 results in a particularly robust cell cycle arrest in G2 phase in AML cells. This study provides a link between the 1,25D-elevated ERK5 pathway and changes in the cell cycle phase transitions in AML cells. Thus, combinations of
vitamin D derivatives and ERK5 inhibitors may be more successful in
cancer clinics than 1,25D or analogs alone. This article is part of a Special Issue entitled '16th
Vitamin D Workshop'.