Sensitivities of human glioma cell lines to interferons and double-stranded RNAs individually and in synergistic combinations

Dick, Robbin S.; Hubbell, Howard R.

doi:10.1007/bf00148390

Cited by 16 publications

(11 citation statements)

References 31 publications

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“…These results also imply that tumor cells that are resistant to the IFN-independent antiproliferative effects of mismatched dsRNA (15,16) may be deficient in a component of the cAMP system. cAMP regulates gene transcription through the phosphorylation of proteins that bind to specific promoter/enhancer sequences known as cAMP-responsive elements.…”

Section: Discussionmentioning

confidence: 88%

“…Combinations of IFN with mismatched dsRNA can synergistically inhibit tumor growth by direct antiproliferative mechanisms (15,16). Similarly, the antitumor effect of IFN-f3 is potentiated by the cAMP phosphodiesterase inhibitor mopidamole (44).…”

Section: Discussionmentioning

confidence: 99%

“…One of the cellular effects of mismatched dsRNA is the inhibition of tumor cell growth, which has been seen both in human tumor cell lines and in fresh human tumor cells in the clonogenic assay (15)(16)(17)(18)(19). However, recent evidence indicates that dsRNAs can inhibit cellular growth independent of IFN induction.…”

Section: Introductionmentioning

confidence: 99%

“…However, recent evidence indicates that dsRNAs can inhibit cellular growth independent of IFN induction. Tumor cells show differential sensitivities to IFNs and dsRNAs, anti-IFN antibodies do not interfere with the antiproliferative effects of dsRNAs, and IFNs and dsRNA can synergistically inhibit tumor cell growth (15)(16)(17)(18). We have utilized a human glioma cell line in which the antiproliferative effects of dsRNAs are not dependent on IFN production to study signal transduction mechanisms.…”

mentioning

confidence: 99%

“…The growth of A1235 cells can be inhibited by natural human IFN-a in a dose-dependent manner (16). Although dsRNA does not induce IFN-a in A1235 cells, the possibility exists that IFN-a may also work through the cAMP system.…”

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confidence: 99%

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Cyclic AMP mediates the direct antiproliferative action of mismatched double-stranded RNA.

Hubbell

Boyer

Roane

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

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Previous experiments have demonstrated that double-stranded RNAs (dsRNAs) can exert an antiproliferative effect on human tumor cells, independent of interferon (lEN) induction. However, the mechanism by which dsRNAs inhibit tumor growth has not been elucidated. As a first step in determining the molecular events responsible for growth arrest, we have explored the role of signal transduction through the cAMP system in the antiproliferative effect of the mismatched dsRNA, r(I),Wr(CI2,U). (Ampligen). These studies utilized the human glioma cell line A1235, which does not produce detectable levels of IFN-a, -P, or -y in response to mismatched dsRNA treatment. Treatment of A1235 cells with mismatched dsRNA in combination with either 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7), which inhibits cAMP-dependent protein kinase and protein kinase C, or N-(2-guanidinoethyl)-5-isoquinolinesulfonamide (HA1004), which preferentially inhibits the cAMP-dependent protein kinase, yielded an antagonism of the mismatched dsRNAinduced antiproliferative effect. Measurement of adenylate cyclase activation showed a dose-dependent increase in activity at antiproliferative mismatched dsRNA concentrations, but not at lower, nonantiproliferative doses. This increase in activity was rapid, seen as early as 30 sec after initiation of treatment, and it was sustained at peak levels for 1-2 hr. Analysis of the intracellular cAMP concentration gave similar kinetics of induction. Exposure of cells to the stable cAMP analogue dibutyryl cAMP yielded dose-dependent inhibition of cell growth. The cAMP phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine also inhibited proliferation. In contrast, neither H-7 nor HA1004 had an effect on growth inhibition induced by human natural IFN-a treatment. In addition, antiproliferative doses of IFN-a did not increase cAMP concentrations. These results indicate that the cAMP system is utilized by mismatched dsRNA as an early signal transduction mechanism for growth control. Furthermore, the antiproliferative effects induced by mismatched dsRNA and IFN can occur by different mechanisms of action.Interferons (IFNs) have pleiotropic effects on cells in both tissue culture and in vivo, including antiviral, antiproliferative, and immunomodulatory effects (1-3). Although the biochemical mechanisms of the actions of IFN are not known, it is known that the effects are receptor mediated (4-6). Since the IFN is degraded shortly after its interaction with the receptor and internalization (4-6), receptorassociated signal transduction mechanisms may play a role in IFN-induced events. Conflicting results have been reported for the role of the cAMP signal transduction system in IFN-induced growth inhibition. Although it has been suggested that IFN-associated increases in intracellular cAMP concentration may mediate the inhibition of DNA synthesis (7,8), other reports have indicated that cAMP is not related to DNA synthesis or growth inhibition (9-13).Double-stranded (ds) RNAs are potent inducers of IFNs (14) an...

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Cyclic AMP mediates the direct antiproliferative action of mismatched double-stranded RNA.

Hubbell

Boyer

Roane

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

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Synergistic interaction between interferon-alpha and interferon-gamma through induced synthesis of one subunit of the transcription factor ISGF3.

et al. 1990

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Interferon‐alpha (IFN alpha) and interferon‐gamma (IFN gamma) each induce in susceptible target cells a state of resistance to viral replication and reduced cellular proliferation, presumably through different mechanisms: these two polypeptides are unrelated by primary sequence and act through distinct cell‐surface receptors to induce expression of largely non‐overlapping sets of genes. However, acting in concert, they can produce synergistic interactions leading to mutual reinforcement of the physiological response. In HeLa cells, this synergistic response was initiated by cooperative induction of IFN alpha stimulated genes (ISGs). These normally quiescent genes were rapidly induced to high rates of transcription following exposure of cells to IFN alpha. Although they were only negligibly responsive to IFN gamma, combined treatment of cells with IFN gamma followed by IFN alpha resulted in an approximately 10‐fold increase in ISG transcription. ISG transcription is dependent upon ISGF3, a positive transcription factor specific for a cis‐acting regulatory element in ISG promoters. IFN gamma treatment induced increased synthesis of latent ISGF3, which was subsequently activated in response to IFN alpha to form approximately 10‐fold higher levels than detected in cells treated with IFN alpha alone. ISGF3 is composed of two distinct polypeptide components, synthesis of one of which was induced by IFN gamma, increasing its cellular abundance from limiting concentrations to a level which allowed formation of at least 10 times as much active ISGF3. Cell lines vary in their constitutive levels of the inducible component of ISGF3 and in the ability of IFNs to increase its synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)

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Cytokine-Based Gene Therapy for Brain Tumors

Sampson¹,

Bigner²,

Dranoff³

1998

Gene Therapy for Neurological Disorders and Brain Tumors

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Sensitivities of human glioma cell lines to interferons and double-stranded RNAs individually and in synergistic combinations

Cited by 16 publications

References 31 publications

Cyclic AMP mediates the direct antiproliferative action of mismatched double-stranded RNA.

Cyclic AMP mediates the direct antiproliferative action of mismatched double-stranded RNA.

Synergistic interaction between interferon-alpha and interferon-gamma through induced synthesis of one subunit of the transcription factor ISGF3.

Cytokine-Based Gene Therapy for Brain Tumors

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