title: 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. This article is part of a Special Issue entitled '16th Vitamin D Workshop'.
authors: Department of Pathology, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 17101, USA.
authors: Xuening
authors: X
authors: Wang
authors: Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel.
authors: Stella
authors: S
authors: Pesakhov
authors: Department of Pathology, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 17101, USA.
authors: Ashley
authors: A
authors: Weng
authors: Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel.
authors: Michael
authors: M
authors: Kafka
authors: Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel.
authors: Elzbieta
authors: E
authors: Gocek
authors: Department of Pathology, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 17101, USA.
authors: Mai
authors: M
authors: Nguyen
authors: Department of Medicine, RWJ Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ 08903, USA.
authors: Jonathan S
authors: JS
authors: Harrison
authors: Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel.
authors: Michael
authors: M
authors: Danilenko
authors: Department of Pathology, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 17101, USA. Electronic address: studzins@njms.rutgers.edu.
authors: George P
authors: GP
authors: Studzinski
mesh_terms: D000818:Animals; D002117:Calcitriol / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D048054:Mitogen-Activated Protein Kinase 7 / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014815:Vitamins / Q000494:pharmacology*
chemical_list: D014815:Vitamins; D048054:Mitogen-Activated Protein Kinase 7; D020928:Mitogen-Activated Protein Kinases; D002117:Calcitriol
keywords: Acute myeloid leukemia (AML); Cell differentiation; ERK1/2; ERK5; MAPK inhibitors; Vitamin D derivatives