Human prostatic cancer cells JCA-1 were induced with a phorbol ester 12-o-tetradecanoylphorbol-13-acetate (TPA), and cell growth differentiation were analyzed. Within hours of exposure to TPA, cell proliferation decreased and reached approximately 80% reduction after 3 days, as determined by [3H]thymidine incorporation and cell counting. Cell cycle analysis revealed a blocking of cells entering into the replicating S and G2M phases from the G1 phase. The TPA induced cells had a reduced growth rate but remained viable. The growth-modulating activity of TPA was similarly observed with LNCaP cells. Agarose gel electrophoresis of the chromosomal DNA from induced cells exhibited a non-fragmented pattern excluding the possibility of cell apoptosis. In parallel to the growth reduction, the TPA induced cells became larger in size showing dendrite like cytoplasmic extensions. Furthermore, JCA-1 cells treated with TPA acquired the expression of cytokeratin 18 and increased the expression of actin and vimentin by 300%. These results indicate an induced growth reduction accompanied by cellular differentiation of the prostatic cancer cells.
Conditioned medium from mitogen stimulated normal peripheral blood lymphocytes (PBL) has been demonstrated to contain a maturation inducer activity mediating the differentiation of human myeloid leukemia cells to monocytes and macrophages. The maturation inducer activity was isolated by salt precipitation, Sepharose CL-6B ion exchange and affinity chromatographies and electrophoresis. Two separate activities with M.W. ranges of 52-56 and 32-35 kDa capable of mediating the terminal differentiation of leukemic HL-60 promyelocytes to monocytes and macrophages were detected. The higher molecular weight species was determined to be a 54 kDa single polypeptide and was found to be distinct from IL-3 and IL-6 by ELISA and differentiation blocking assay. The inducing activity of the 32-35 kDa material was largely neutralized after treatment with anti-IL-3, but not with other antibodies. Employing the immunofluorescent antibody technique, the 54 kDa protein was detected on the surface membranes of PBL. The proportions and number of maturation inducer bearing lymphocytes in patients with acute myelogenous leukemia (0.4% and 35/mm3, respectively) were significantly lower than that of healthy donors (7.9% and 178/mm3) The role of these physiological factors in leukemia cell differentiation is discussed.
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