Adenylate Cyclase/cAMP Pathway Downmodulation Counteracts Apoptosis Induced by IFN-<i>α</i>in Human Epidermoid Cancer Cells

Naviglio, Silvio; Spina, Annamaria; Marra, Monica; Sorrentino, Angela; Chiosi, Emilio; Romano, Maria; Improta, Salvatore; Budillon, Alfredo; Illiano, G.; Abbruzzese, Alberto; Caraglia, Michele

doi:10.1089/jir.2006.0101

Cited by 15 publications

(6 citation statements)

References 42 publications

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“…As shown in Figure 5, we found that exposure of cells to forskolin resulted in a significant time-dependent decrease of ERK1/2 activity that was almost completely abrogated at 6 h. CREB protein, a major substrate of PKA, is strongly phosphorylated in response to forskolin. 16,32 As expected, the treatment of cancer cells with forskolin determined a time-dependent increase of CREB phosphorylation (Fig. 5).…”

Section: Leptin Induces Proliferative Effect In Mda-mb-231 Cellssupporting

confidence: 82%

Leptin enhances growth inhibition by cAMP elevating agents through apoptosis of MDA-MB-231 breast cancer cells

Naviglio

D²,

Romano³

et al. 2009

Cancer Biology & Therapy

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Elevation of cAMP inhibits the proliferation and expression of transformed phenotype in several cell types, including breast cancer cells. Leptin has been shown to act as a mitogen/survival factor in many types of cancer cells. In the present work, we have studied the impact of cAMP elevation on leptin-induced proliferation of breast cancer cells. Here we report that treatment of estrogen receptor negative human breast cancer cell line MDA-MB-231 with leptin or cAMP elevating agents has positive and negative effects on cell proliferation, respectively. Surprisingly, we find that leptin strongly potentiates the anti-proliferative action of cAMP elevating agents, by concurring to cell cycle arrest at G1 phase and inducing apoptosis. Pretreatment with the PKA inhibitor KT-5720 completely prevented the anti-proliferative effects induced by the combination between leptin and cAMP elevating agents. The above anti-proliferative effects were paralleled by the decrease of cyclin D1 and A and by the increase of inhibitor p27kip1 cell cycle regulating protein levels. In these conditions we found also a strong decrease of anti-apopotic Bcl2 protein levels. Altogether, our data extend the evidence of adenylate cyclase/cAMP/PKA as a growth suppressor system and of leptin as a growth promoting factor in breast cancer cells. Remarkably, our results suggest that when cAMP levels are increased, leptin drives cells towards apoptosis, and that targeting both cAMP levels and leptin signalling might represent a simple novel way for therapeutic intervention in breast cancer.

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Section: Leptin Induces Proliferative Effect In Mda-mb-231 Cellssupporting

confidence: 82%

Leptin enhances growth inhibition by cAMP elevating agents through apoptosis of MDA-MB-231 breast cancer cells

Naviglio

D²,

Romano³

et al. 2009

Cancer Biology & Therapy

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“…Such a differential effect must be considered whenever an immortalized cell line is used as a model since tumor cells often develop resistance to the death-inducing effects of Type I interferons [15]–[18]. Indeed, Jurkat CD4 + T cells do not undergo they typical cell cycle arrest or apoptotic response generally associated with IFNα treatment [19], consistent with the altered IFNα response described herein.…”

Section: Discussionsupporting

confidence: 72%

Differential Response of Primary and Immortalized CD4+ T Cells to Neisseria gonorrhoeae-Induced Cytokines Determines the Effect on HIV-1 Replication

et al. 2011

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To compare the effect of gonococcal co-infection on immortalized versus primary CD4+ T cells the Jurkat cell line or freshly isolated human CD4+ T cells were infected with the HIV-1 X4 strain NL4-3. These cells were exposed to whole gonococci, supernatants from gonococcal-infected PBMCs, or N. gonorrhoeae-induced cytokines at varying levels. Supernatants from gonococcal-infected PBMCs stimulated HIV-1 replication in Jurkat cells while effectively inhibiting HIV-1 replication in primary CD4+ T cells. ELISA-based analyses revealed that the gonococcal-induced supernatants contained high levels of proinflammatory cytokines that promote HIV-1 replication, as well as the HIV-inhibitory IFNα. While all the T cells responded to the HIV-stimulatory cytokines, albeit to differing degrees, the Jurkat cells were refractory to IFNα. Combined, these results indicate that N. gonorrhoeae elicits immune-modulating cytokines that both activate and inhibit HIV-production; the outcome of co-infection depending upon the balance between these opposing signals.

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“…2A and B). Adenosine 3',5'-cyclic monophosphate (cAMP) is a second messenger with pro-apoptotic effects in some cells, and analogs of cyclic AMP are known to induce differentiation and apoptosis in several tumor types, including breast,70 colon,70 epidermoid,71 ovarian,72 pancreatic cancer73 and retinoblastoma 74. While we did not perform microarray analyses on dibutyryl cyclic AMP treated RCC lines, these data indicate that cyclic AMP analogs could be efficacious in RCC treatment.…”

Section: Discussionmentioning

confidence: 99%

Gene microarray analysis of human renal cell carcinoma: The effects of HDAC inhibition and retinoid treatment

Tavares¹,

Nanus²,

Yang³

et al. 2008

Cancer Biology & Therapy

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Histone deacetylase (HDAC) inhibitor treatments can augment the anti-tumor effects of retinoids in renal cancer cells. We studied the effects of the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) and 13-cis retinoic acid (cRA) on two human renal cell carcinoma (RCC) lines. Cells were cultured in the presence of each drug for six days to determine the responses to monotherapy and to combination therapy. The proliferation of SKRC06 was inhibited with cRA treatment; the proliferation of SKRC39 was not. However, both RCC lines were sensitive to growth inhibition by dibutyryl cyclic AMP, with or without 13-cis RA. SAHA alone alone reduced cell proliferation in both cell lines. To identify the alterations in gene expression that correlate with the responsiveness to treatment, gene microarray analyses were performed. Several retinoid-regulated genes exhibited much higher mRNA levels in SKRC06 than in SKRC39, even in the absence of drugs; these included crabp2, rarγ and cyp26A1. Combination treatment of cells with both SAHA and cRA induced several transcripts with known anti-cancer/immunomodulatory effects, including dhrs9, gata3, il1β, phlda1, txk and vhl. Immunostaining confirmed the decreased expression of gata3 in human RCC specimens compared to normal kidney. Together, our results show that treatment of RCC with cRA and/or SAHA increases the expression of several genes and gene families that result in reduced cell proliferation.

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Adenylate Cyclase/cAMP Pathway Downmodulation Counteracts Apoptosis Induced by IFN-αin Human Epidermoid Cancer Cells

Cited by 15 publications

References 42 publications

Leptin enhances growth inhibition by cAMP elevating agents through apoptosis of MDA-MB-231 breast cancer cells

Leptin enhances growth inhibition by cAMP elevating agents through apoptosis of MDA-MB-231 breast cancer cells

Differential Response of Primary and Immortalized CD4+ T Cells to Neisseria gonorrhoeae-Induced Cytokines Determines the Effect on HIV-1 Replication

Gene microarray analysis of human renal cell carcinoma: The effects of HDAC inhibition and retinoid treatment

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