vasoactive-intestinal-peptide and Leukemia--Promyelocytic--Acute

Ghrelin is a 28 amino acid peptide hormone that is mainly produced by the stomach, but also by several tissues and tumors. Ghrelin is octanoylated on the Ser(3), but is also detected as a des-acylated form. Only the acylated ghrelin activates the GH secretagogue receptor (GHS-R) type 1a to stimulate GH release, and regulate food intake and energy metabolism. For the first time, we report that ghrelin and des-acyl ghrelin are present in human promyelocytic HL-60, monocytic THP-1 and lymphoblastic SupT1 cell lines. The human leukemic cell lines did not express the functional GHS-R 1a, whereas they expressed GHS-R 1b, a truncated variant of the receptor. Leukemic cell proliferation was not modified by the addition of octanoylated or des-acyl ghrelins. However, THP-1 and HL-60 cell proliferations were inhibited by SB801, an antibody directed against the N-terminal octanoylated portion of ghrelin, suggesting that octanoylated ghrelin stimulates cell proliferation via an autocrine pathway involving an as yet unidentified ghrelin receptor. Both octanoylated and des-acyl ghrelins did not alter the basal adenylate cyclase activity. Treatments of THP-1 and SupT1 cells by both octanoylated and des-acyl ghrelins did not modify the adenylate cyclase activity in response to vasoactive intestinal peptide, suggesting that ghrelin is unlikely to modulate the anti-inflammatory and differentiating properties of vasoactive intestinal peptide.

Topics: Adenylyl Cyclases; Autocrine Communication; Carboxylesterase; Cell Line, Tumor; Cell Proliferation; Ghrelin; HL-60 Cells; Humans; Leukemia; Leukemia, Lymphoid; Leukemia, Monocytic, Acute; Leukemia, Promyelocytic, Acute; Peptide Hormones; Receptors, G-Protein-Coupled; Receptors, Ghrelin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Vasoactive Intestinal Peptide

Neuroblastoma, a tumor of the sympathetic nervous system, is the most common solid malignancy of childhood outside the central nervous system. Vasoactive intestinal peptide (VIP) is produced by some of these tumors, and elevated serum levels correlate with tumor cell differentiation and a favorable prognosis. It has previously been demonstrated that human neuroblastoma cell lines LA-N-5 and IMR-32 will differentiate in vitro when exposed to retinoic acid. It is now shown that VIP also induces in vitro differentiation of these neuroblastoma lines. LA-N-5 or IMR-32 cells were grown in the presence of different concentrations of VIP. Cell proliferation was suppressed, as measured by cell count, incorporation of [3H]thymidine, and measurement of the proliferation index. The degree of suppression correlated with the concentration of VIP, and the effect was indistinguishable, on a molar basis, from that seen when cells were treated with retinoic acid. Similarly, the morphological changes seen in the VIP-treated cells were the same as those seen in retinoic acid-treated ones. The effects of VIP on both cell lines, like those of retinoic acid, are reversible. The human neuroepithelioma line CHP-100, is much less sensitive to either agent. Vasoactive intestinal peptide is the first substance shown to cause differentiation of neuroblastoma cells in vitro which is also known clinically to have a specific association with that tumor. It is postulated that VIP may play a key role in the well-documented maturation of these tumors in vivo and in the normal development of the sympathetic nervous system. These findings may also have therapeutic implications for the management of this frustrating childhood malignancy.

Topics: Breast Neoplasms; Cell Differentiation; Cell Division; Cell Line; Dose-Response Relationship, Drug; Female; Humans; Kinetics; Leukemia, Promyelocytic, Acute; Neuroblastoma; Neuroectodermal Tumors, Primitive, Peripheral; Tumor Cells, Cultured; Vasoactive Intestinal Peptide