A classical PKA inhibitor increases the oncolytic effect of M1 virus via activation of exchange protein directly activated by cAMP 1

Li, Kai; Liang, Jiankai; Lin, Yongcheng; Zhang, Haipeng; Xiao, Xiao; Tan, Yaqian; Cai, Jing; Zhu, Wenbo; Xing, Fan; Hu, Jun; Gao, Yan

doi:10.18632/oncotarget.10305

Cited by 22 publications

(18 citation statements)

References 47 publications

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“…This fact has also prompted us to test whether combining M1 with various chemical compounds enhances the oncolytic effect in refractory tumor cells in which M1 inhibits less than 25% of cell viability (15). For example, we recently reported that the activation of cyclic adenosine monophosphate (cAMP) and exchange protein directly activated by cAMP1 (Epac1) signaling pathways enhances the oncolytic effect of M1 (15,16), which supports our hypothesis.…”

supporting

confidence: 79%

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Selective replication of oncolytic virus M1 results in a bystander killing effect that is potentiated by Smac mimetics

Cai

Lin

Zhang

et al. 2017

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

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Oncolytic virotherapy is a treatment modality that uses native or genetically modified viruses that selectively replicate in and kill tumor cells. Viruses represent a type of pathogen-associated molecular pattern and thereby induce the up-regulation of dozens of cytokines via activating the host innate immune system. Second mitochondria-derived activator of caspases (Smac) mimetic compounds (SMCs), which antagonize the function of inhibitor of apoptosis proteins (IAPs) and induce apoptosis, sensitize tumor cells to multiple cytokines. Therefore, we sought to determine whether SMCs sensitize tumor cells to cytokines induced by the oncolytic M1 virus, thus enhancing a bystander killing effect. Here, we report that SMCs potentiate the oncolytic effect of M1 in vitro, in vivo, and ex vivo. This strengthened oncolytic efficacy resulted from the enhanced bystander killing effect caused by the M1 virus via cytokine induction. Through a microarray analysis and subsequent validation using recombinant cytokines, we identified IL-8, IL-1A, and TRAIL as the key cytokines in the bystander killing effect. Furthermore, SMCs increased the replication of M1, and the accumulation of virus protein induced irreversible endoplasmic reticulum stress-and c-Jun N-terminal kinase-mediated apoptosis. Nevertheless, the combined treatment with M1 and SMCs had little effect on normal and human primary cells. Because SMCs selectively and significantly enhance the bystander killing effect and the replication of oncolytic virus M1 specifically in cancer cells, this combined treatment may represent a promising therapeutic strategy.oncolytic virus | SMAC mimetics | bystander killing effect

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supporting

confidence: 79%

“…We have previously shown that cancerselective replication underlies the cancer targeting property of M1 (6,15,16). To understand whether the replication of M1 virus is affected by SMCs, we analyzed the effect of SMCs on the replication of M1 virus.…”

Section: C-iap1 and C-iap2 Play Key Roles In The Enhanced Oncolytic Ementioning

confidence: 99%

Selective replication of oncolytic virus M1 results in a bystander killing effect that is potentiated by Smac mimetics

Cai

Lin

Zhang

et al. 2017

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

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“…The effects of cAMP that are not accounted for by the use of PKA inhibitors are not to be disregarded, as they could have specific roles in the cellular response to potentially confounding signals. The choice between PKA and EPAC1 as an effector thus could possibly be determined, not only by the expression pattern of these molecules but also possibly by the spatial and temporal compartmentalization of cAMP, which could have differential effects, as recently documented for b2AR [103][104][105].…”

Section: Effector Pathways-pka and Epac1mentioning

confidence: 96%

cAMP: a multifaceted modulator of immune synapse assembly and T cell activation

Arumugham

Baldari

2017

Journal of Leukocyte Biology

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T Lymphocyte activation involves a substantial reorganization of the membranous and intracellular compartments. Signaling complexes assemble and dismantle in a highly ordered fashion in both compartments and orchestrate the activation of T cells with high sensitivity and specificity. TCR ligation leads to a short burst of cAMP production, which is centrally required for T cell activation; however, sustained elevations in intracellular cAMP concentrations are immunosuppressive. Emerging evidence of the existence of local cAMP pools gleaned from studies on other cell types suggests that cAMP compartmentalization may account, in part, for these opposing effects. Whereas cAMP compartmentalization has been identified as a central factor in the control of the cAMP-dependent processes in other cell types, this has, as yet, not been addressed in T lymphocytes. In this review, we discuss the role of cAMP in T cell activation and differentiation, with an emphasis on the effects mediated by the cAMP effectors, protein kinase A (PKA) and exchange protein activated by cAMP (EPAC)1, and on the regulatory proteins that may control the generation of local cAMP pools in T cells. We also present an overview of the available tools to image cAMP production at the subcellular level and discuss how bacterial adenylate cyclase (AC) toxins that are known to generate local cAMP pools can be exploited to address the role of cAMP compartmentalization in T cell activation.

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“…In general, EPAC and PKA mediated signaling pathways function antagonistically, independently or synergistically in rare occasions to modulate cancer cell proliferation, apoptosis, adhesion, and migration (193,361,473,474,722,1030,1073). Activation of cAMP/EPAC1 signaling pathways has also been reported to sensitize refractory cancer cells to oncolytic virotherapy (605,606).…”

Section: B Role Of Epac In Cancersmentioning

confidence: 99%

Intracellular cAMP Sensor EPAC: Physiology, Pathophysiology, and Therapeutics Development

Robichaux

Cheng

2018

Physiological Reviews

159

226

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This review focuses on one family of the known cAMP receptors, the exchange proteins directly activated by cAMP (EPACs), also known as the cAMP-regulated guanine nucleotide exchange factors (cAMP-GEFs). Although EPAC proteins are fairly new additions to the growing list of cAMP effectors, and relatively "young" in the cAMP discovery timeline, the significance of an EPAC presence in different cell systems is extraordinary. The study of EPACs has considerably expanded the diversity and adaptive nature of cAMP signaling associated with numerous physiological and pathophysiological responses. This review comprehensively covers EPAC protein functions at the molecular, cellular, physiological, and pathophysiological levels; and in turn, the applications of employing EPAC-based biosensors as detection tools for dissecting cAMP signaling and the implications for targeting EPAC proteins for therapeutic development are also discussed.

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A classical PKA inhibitor increases the oncolytic effect of M1 virus via activation of exchange protein directly activated by cAMP 1

Cited by 22 publications

References 47 publications

Selective replication of oncolytic virus M1 results in a bystander killing effect that is potentiated by Smac mimetics

Selective replication of oncolytic virus M1 results in a bystander killing effect that is potentiated by Smac mimetics

cAMP: a multifaceted modulator of immune synapse assembly and T cell activation

Intracellular cAMP Sensor EPAC: Physiology, Pathophysiology, and Therapeutics Development

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