ERK 5/MAPK pathway has a major role in 1α,25-(OH)2 vitamin D3-induced terminal differentiation of myeloid leukemia cells

Abstract

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.

The MAPK ERK5, but not ERK1/2, inhibits the progression of monocytic phenotype to the functioning macrophage

“…We have previously observed that the exposure of AML cells to 1,25D in the presence of BIX02189 or XMD8-92 markedly reduces the surface expression of CD14, the principal marker of monocytic differentiation [27, 28]. As mentioned above, this was accompanied by an increase in the expression of CD11b, the general myeloid marker [43], raising the possibility that the inhibition of the ERK5 pathway results in a switch in the differentiation lineage.…”

“…Interestingly, ERK5, a known downstream target of COT1 was also activated, and its inhibition appeared to alter the expression of conventional markers in 1,25D-induced differentiation of several types of cultured AML cell [27, 28]. Although the activation of ERK5 was paralleled by the expression of several markers of monocytic differentiation, there was a reciprocal modulation of the relative levels of these markers, with general myeloid marker CD11b being increased by the addition of inhibitors of the ERK5 pathway to either untreated or 1,25D-treated AML cells, while the specific monocytic marker CD14 was concurrently decreased.…”

Epidermal growth factor receptor expression affects proliferation and apoptosis in non-small cell lung cancer cells via the extracellular signal-regulated kinase/microRNA 200a signaling pathway

“…ERK is a protein kinase that is located in the terminal position in the signaling pathway of mitogen-activated protein kinase (MAPK), and forms p-ERK via phosphorylation (23). p-ERK may influence the transcriptional expression of associated genes, is associated with cell proliferation and serves a crucial function in malignant transformation.…”

The MEK5/ERK5 signalling pathway in cancer: a promising novel therapeutic target

“…However, in contrast with previous studies, it was also demonstrated that pharmacological inhibition of ERK5 signalling by XMD8-92 and BIX02189 in 1,25D-induced differentiating AML cells resulted in particularly robust cell cycle arrest at G2 phase and monocytic differentiation. Therefore, in this latter study, the use of ERK5 inhibitors in combination with vitamin D derivatives was suggested as a potential successful therapeutic approach in AML [66].…”

“…Currently, a vitamin D3 derivative, 1a,25(OH) 2 vitamin D3 (1,25D), and its synthetic analogues, have been used to promote the differentiation of leukaemic cell lines, with promising antileukaemic action. Nevertheless, clinical trials with these compounds remain inconclusive [66].…”