Growth inhibition of Friend erythroleukaemia cell tumours in vivo by a synthetic analogue of prostaglandin A: an action independent of natural killer-activity

Marini, Stefano; Palamara, Anna Teresa; Garaci, Enrico; Santoro, M.

doi:10.1038/bjc.1990.86

Cited by 7 publications

(1 citation statement)

References 24 publications

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“…These metabolites of PGE1 and PGE2, respectively, are characterized by the presence of an a,I-unsaturated carbonyl group in the cyclopentenone ring which is believed to be the active moiety in suppressing growth (3,19,24,33). They have been found to inhibit the growth of B16 melanoma and Friend erythroleukemia virus-infected cells in vivo as well as in vitro, suggesting their utility as effective antineoplastic agents (15,26,39). They are actively taken up by cells via a specific carrier on the cell membrane and are transported to the nucleus, where they associate with nuclear proteins (30)(31)(32).…”

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Induction of HSP70 gene expression by the antiproliferative prostaglandin PGA2: a growth-dependent response mediated by activation of heat shock transcription factor.

Holbrook¹,

Carlson²,

Choi³

et al. 1992

Mol. Cell. Biol.

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Prostaglandins (PG) of the A series are potent inhibitors of cell proliferation. Recently, it was shown that PGA2-induced growth arrest was associated with the increased synthesis of stress proteins encoded by the HSP70 gene family. In this study, we have examined the molecular basis for this increased HSP70 expression. Northern (RNA) blot analysis and nuclear run-on assays demonstrated that induction of high levels of HSP70 mRNA results from an increase in the rate of transcription. High-level induction is specific to the HSP70 family of heat shock proteins and is rapid, reversible, dose dependent, and specific for PGs capable of growtharresting HeLa cells. In addition, the response was found to be highly dependent on the growth state of the cells, as induction occurs in growing but not in confluent nongrowing cell populations. Induction is dependent on the activation of heat shock factor. Cycloheximide pretreatment, which inhibits the antiproliferative effects of PGA2, prevents activation of the heat shock factor and induction of HSP70 mRNA by PGA2. These results support a role for HSP70 in mediating the antiproliferative effects of PGA2.The cyclopentenone prostaglandins (PG) PGA1 and PGA2 have been shown to be potent inhibitors of proliferation in a variety of cultured cells (2-4, 15, 37). These metabolites of PGE1 and PGE2, respectively, are characterized by the presence of an a,I-unsaturated carbonyl group in the cyclopentenone ring which is believed to be the active moiety in suppressing growth (3,19,24,33). They have been found to inhibit the growth of B16 melanoma and Friend erythroleukemia virus-infected cells in vivo as well as in vitro, suggesting their utility as effective antineoplastic agents (15,26,39). They are actively taken up by cells via a specific carrier on the cell membrane and are transported to the nucleus, where they associate with nuclear proteins (30-32). They affect cell cycle progression in two ways. They act on cells at any stage of the cell cycle to cause a general decrease in the rate of progression, and they act specifically on cells in the G1 phase to arrest progression (2, 35). Growth arrest has been associated with a decline in both c-myc and N-myc expression (22,27). However, the exact mechanism by which PGs control proliferation is largely unknown.The heat shock protein 70 (HSP70) gene family is part of a larger set of proteins whose syntheses are increased in response to a variety of chemical and biological stresses (25,40). The expression of these genes follows the stress-induced activation of one or more heat shock transcription factors (HSF) which bind to a specific DNA sequence, the heat shock element (HSE), in the promoter regions of the HSP genes to increase their rates of transcription (36,41,42). There is also evidence to suggest that there are both positive and negative roles for HSPs in normal cell growth and differentiation. For example, certain HSPs have been shown to be induced in response to proliferative stimuli (12,44 (20,21,23).Recently, two groups have re...

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