Inhibition of STAT3 signaling induces apoptosis and decreases survivin expression in primary effusion lymphoma

Aoki, Yoshiyasu; Feldman, Gerald M.; Tosato, Giovanna

doi:10.1182/blood-2002-07-2130

Cited by 421 publications

(356 citation statements)

References 55 publications

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“…Survivin, an inducible member of the IAP family, is abundant in cancers and tissues that contain proliferating cells (17,18). STAT3 binds to the survivin promoter, and inhibition of STAT3 signaling reduces survivin expression (19,20). In these experiments, we found that survivin mediates a necessary virus-enhancing effect of STAT3 activation on VZV, a lytic herpesvirus.…”

mentioning

confidence: 53%

Signal transducer and activator of transcription 3 (STAT3) and survivin induction by varicella-zoster virus promote replication and skin pathogenesis

Sen¹,

Che²,

Rajamani³

et al. 2011

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

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Varicella-zoster virus (VZV) is a human α-herpesvirus that causes varicella (chickenpox) during primary infection and zoster (shingles) upon reactivation. Like other viruses, VZV must subvert the intrinsic antiviral defenses of differentiated human cells to produce progeny virions. Accordingly, VZV inhibits the activation of the cellular transcription factors IFN regulatory factor 3 (IRF3) and signal transducers and activators of transcription 1 (STAT1), thereby downregulating antiviral factors, including IFNs. Conversely, in this study, we found that VZV triggers STAT3 phosphorylation in cells infected in vitro and in human skin xenografts in SCID mice in vivo and that STAT3 activation induces the anti-apoptotic protein survivin. Small-molecule inhibitors of STAT3 phosphorylation and survivin restrict VZV replication in vitro, and VZV infection of skin xenografts in vivo is markedly impaired by the administration of the phospho-STAT3 inhibitor S3I-201. STAT3 and survivin are required for malignant transformation caused by γ-herpesviruses, such as Kaposi's sarcoma virus. We show that STAT3 activation is also critical for VZV, a nononcogenic herpesvirus, via a survivin-dependent mechanism. Furthermore, STAT3 activation is critical for the life cycle of the virus because VZV skin infection is necessary for viral transmission and persistence in the human population. Therefore, we conclude that takeover of this major cell-signaling pathway is necessary, independent of cell transformation, for herpesvirus pathogenesis and that STAT3 activation and up-regulation of survivin is a common mechanism important for the pathogenesis of lytic as well as tumorigenic herpesviruses.T he life cycle of varicella-zoster virus (VZV) in the human host depends on its tropism for T cells, skin, and neurons within sensory ganglia (1). As shown in the SCID mouse model of VZV pathogenesis, infected human T cells transport the virus to epidermal cells in human skin xenografts and to neural cells in dorsal root ganglia xenografts (2, 3). VZV establishes latency in sensory ganglia; upon reactivation, the virus migrates to the skin via axonal transport to cause zoster.VZV modulates several signaling pathways to replicate efficiently in vitro, and these regulatory effects are especially important in differentiated skin cells infected in vivo. VZV interferes with IFN induction and signaling via inhibition of IFN regulatory factor 3 (IRF3), NFκB, and STAT1 in vitro and in skin (4, 5). However, the pathogenesis of VZV skin infection requires a mechanism to overcome the constitutive IFNα expression by epidermal cells that accounts for the 10-to 21-d interval between VZV transfer into skin and the appearance of lesions at skin surfaces (6). How VZV overcomes this cutaneous IFN barrier and produces skin vesicles is not known.The STATs are ubiquitous transcription factors with many cellular functions and are at the junction of several cytokinesignaling pathways (7,8). Of the seven STAT family proteins, STAT3 exerts widespread effects through transcri...

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mentioning

confidence: 53%

Signal transducer and activator of transcription 3 (STAT3) and survivin induction by varicella-zoster virus promote replication and skin pathogenesis

Sen¹,

Che²,

Rajamani³

et al. 2011

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

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“…STAT3 directly binds to and regulates the survivin promoter, 63 and STAT3 activation induces survivin expression and rescues cells from apoptosis. 25,63 However, survivin can also bind to STAT3 dimers and repress STAT3 transactivation of target gene promoters. 64 Thus, clarifying the mechanism underlying the association of STAT3-survivin coexpression with better overall survival and progression-free survival is difficult.…”

Section: Discussionmentioning

confidence: 99%

“…23 Signal transducer and activator of transcription 3 (STAT3) and p53 proteins regulate survivin expression. 24,25 Cyclin-dependent kinase1 and heat shock protein 90 participate in posttranslational modifications of survivin by regulating survivin's stability. 26,27 Survivin is expressed during fetal development but is undetectable in normal terminally differentiated adult tissues.…”

mentioning

confidence: 99%

Prognostic and biological significance of survivin expression in patients with diffuse large B-cell lymphoma treated with rituximab-CHOP therapy

et al. 2015

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Survivin, a member of the inhibitor of apoptosis protein family, is overexpressed in a variety of human neoplasms. The prognostic significance of survivin expression in diffuse large B-cell lymphoma patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) is unclear. We used standard immunohistochemistry methods to quantify survivin expression in 463 patients with de novo diffuse large B-cell lymphoma who received the R-CHOP. Of the 463 patients, 269 (58%) had survivin overexpression with a cutoff of 425%, associated with an International Prognostic Index score of 42 (P = 0.015), disease in ≥ 2 extranodal sites (P = 0.011), and a high Ki-67 index (Po 0.0001). Among patients with activated B cell-like disease, the overall survival rate of survivin-positive patients was significantly lower than that of survivinnegative patients (P = 0.033); multivariate analysis confirmed that in these patients, survivin overexpression was an independent prognostic factor for survival. Among patients with wild-type p53 overexpression, the overall survival and progression-free survival rates of the survivin-positive group were significantly lower than those of the survivin-negative group (P = 0.035 and P = 0.04 respectively). In STAT3-positive patients, survivin overexpression was associated with significantly better survival. Among patients with activated B cell-like disease, survivin-positive compared with survivin-negative groups had significantly different gene expression signatures, including genes involved in mitosis or tumor cell proliferation. Our results indicate that survivin is an

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“…27 A number of genes have been identified as STAT targets and have been suggested to mediate STAT-dependent processes (Table 1). STAT3 targets that may mediate cell survival effects include several bcl-2 family members, 20,39,40 the IAP protein surviving, 41 and the serine/threonine kinases pim-1 and pim-2. 42 STAT3 contributes to cell survival by collaborating with c-jun to repress transcription of the pro-apoptotic cytokine Fas.…”

Section: Stat Signaling and Cancermentioning

confidence: 99%

Genome-wide analysis of STAT target genes: Elucidating the mechanism of STAT-mediated oncogenesis

Alvarez

Frank²

2004

Cancer Biology & Therapy

104

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Inhibition of STAT3 signaling induces apoptosis and decreases survivin expression in primary effusion lymphoma

Cited by 421 publications

References 55 publications

Signal transducer and activator of transcription 3 (STAT3) and survivin induction by varicella-zoster virus promote replication and skin pathogenesis

Signal transducer and activator of transcription 3 (STAT3) and survivin induction by varicella-zoster virus promote replication and skin pathogenesis

Prognostic and biological significance of survivin expression in patients with diffuse large B-cell lymphoma treated with rituximab-CHOP therapy

Genome-wide analysis of STAT target genes: Elucidating the mechanism of STAT-mediated oncogenesis

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