Lipoxygenase metabolism is required for interleukin‐3 dependent proliferation and cell cycle progression of the human M‐07e cell line

Abstract

The cell line M-07e requires either Interleukin-3 (IL-3) or granulocyte-macrophage colony stimulating factor (GM-CSF) for proliferation in vitro. Cells deprived of growth factor for up to 48 hours remain viable but no longer divide. The growth-factor-deprived M-07e cells begin to divide within 48 hours of reexposure to IL-3. Flow cytometric analysis of M-07e cells labeled with hypotonic propidium iodide demonstrates that the percentage of cells undergoing DNA synthesis decreases from 24%, in a log phase population of IL-3 stimulated cells, to 1% when cells are deprived of IL-3 for 24 hours. IL-3-deprived cells accumulate predominantly in a flow cytometry peak representative of G0/G1. DNA synthetic activity, as determined by tritiated thymidine uptake and flow cytometry, resumes between 12 and 18 hours after reexposure to IL-3, reaching a peak of up to 40% by 24 hours and returning to log phase levels by 72 hours. Prior to initiation of DNA synthesis, increases are seen in mRNA levels for five-lipoxygenase-activating protein (FLAP). Following reexposure to IL-3, a rapid time-dependent biosynthesis of leukotriene D4 (LTD4) is induced by M-07e cells. When IL-3 is added in the presence of any of three lipoxygenase inhibitors tested (Piriprost, caffeic acid, nordihydroguiaretic acid) or FLAP inhibitor, MK-886, there is dose-dependent inhibition of the resumption of proliferation and of DNA synthesis. Flow cytometric cell cycle analysis demonstrates that the inhibited cells remain in the G0/G1 population and do not progress through the cell cycle. These results are consistent with our previous observation that an intact lipoxygenase pathway is necessary for hematopoietic growth-factor-stimulated colony formation of normal bone marrow myeloid progenitors and suggest that the induction of a lipoxygenase metabolite or metabolites is necessary for myeloid cells to progress through the cell cycle when stimulated by a hematopoietic growth factor.

5-Lipoxygenase and human pulmonary artery endothelial cell proliferation

“…A number of studies have also shown a role for 5LO in cell proliferation, although the effect of the enzyme on cell growth is cell-type specific: [5LO facilitates the growth of lung carcinoma (7,38), adenocarcinoma of the prostate (5,22,25), pancreatic adenocarcinoma (17), adenocarcinoma of the colon (26), and chronic myelogenous leukemia (3)], but it suppresses the growth of other cells, including glioma (21,32), adenocarcinoma of the breast (36), and murine Leydig cell tumors (33). In addition, 5LO has been found to mediate cytokine-induced lymphocyte (30) and murine thymocyte (40) growth and to facilitate epidermal cell proliferation (12).…”