prostaglandin-a1 and Leukemia--Erythroblastic--Acute

Prostaglandins of the A type (PGAs) function as signals for heat shock protein (hsp) synthesis in mammalian cells. In human K562 erythroleukemic cells, PGA1 induces the synthesis of a M(r) 70,000 hsp (hsp70) by cycloheximide-sensitive activation of heat shock transcription factor (HSF). Induction of hsp70 has been associated recently with the ability of PGA to protect K562 cells from thermal injury, establishing a thermotolerant state; however, the role of hsp70 in thermotolerance is still controversial. Because quercetin was shown to modulate hsp70 expression after heat shock in K562 cells, we have investigated the effect of this flavonoid on HSF activation, hsp70 synthesis, and thermotolerance in human K562 cells after induction with PGA1. Quercetin was found to inhibit hsp70 synthesis for a period of 3-6 h after PGA1 treatment. This transient block was exerted at the transcriptional level and was not due to the loss of HSF DNA-binding activity. After the initial delay, hsp70 synthesis reached the same rate as the PGA1-treated control, and it was actually prolonged in the presence of quercetin. In PGA1-treated cells, quercetin suppressed PGA1-induced thermotolerance completely if the heat shock was applied at a time (6 h) when hsp70 synthesis was inhibited, whereas it could not prevent the establishment of a thermotolerant state if the heat challenge was applied 24 h after treatment, when hsp70 synthesis was not affected. These results support strongly the hypothesis that hsp70 is involved in the establishment of thermotolerance in human cells.

Topics: Dose-Response Relationship, Drug; Drug Antagonism; HSP70 Heat-Shock Proteins; Humans; Leukemia, Erythroblastic, Acute; Prostaglandins A; Quercetin; Temperature; Tumor Cells, Cultured

Topics: Cell Division; Cell Line; Humans; Leukemia, Erythroblastic, Acute; Molecular Weight; Neoplasm Proteins; Prostaglandins; Prostaglandins A

Among several prostaglandins (PGs) tested, PGF1 alpha was found to slightly enhance, while PGAs and PGDs were found to drastically inhibit the growth of K562 cells in culture. This effect was dose dependent. While PGD2 was cytotoxic, PGA1 treatment could totally inhibit K562 cell proliferation, without affecting cell viability. PGA1 action was reversible; however, K562 cells totally lost their growth potential after prolonged exposure to PGAs. While it did not significantly affect DNA and RNA synthesis, PGA1 partially inhibited protein synthesis and glycosylation in these cells. In particular, the production of two polypeptides with molecular weights of 92,000 and 46,000, respectively, was decreased, while the synthesis of a protein with a molecular weight of 74,000 was induced. These results strongly support the concept that PGs are involved in the regulation of cell proliferation, and that PGs containing a reactive alpha, beta-unsaturated carbonyl group in the cyclopentane ring are potential antineoplastic agents.

Topics: Bucladesine; Cell Division; Cell Line; DNA; Humans; Leukemia, Erythroblastic, Acute; Prostaglandins; Prostaglandins A; Protein Biosynthesis; RNA