Autophagic Cell Death of Malignant Glioma Cells Induced by a Conditionally Replicating Adenovirus

Ito, Hiroki; Aoki, Hiroshi; Kühnel, Florian; Kondo, Yasuko; Kubicka, Stefan; Wirth, Thomas; Iwado, Eiji; Iwamaru, Arifumi; Fujiwara, Keishi; Hess, Kenneth R.; Lang, Frederick F.; Sawaya, Raymond; Kondo, Seiji

doi:10.1093/jnci/djj161

Cited by 155 publications

(160 citation statements)

References 53 publications

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“…In contrast, in a more recent publication, an hTERT-Ad vector was shown to induce autophagic cell death in tumor cells (22). In this study, our aim was to explore the role of the survivin promoter in CRAd mediated oncolysis of human glioma.…”

Section: Introductionmentioning

confidence: 91%

“…Autophagy was assessed in No. 10 cells by the quantification of acidic vesicular organelles with supravital cell staining using acridine orange, as described previously (22,25). Cells were grown in square coverslips 24 h before infection.…”

Section: Cell Cycle Analysismentioning

confidence: 99%

“…The PI3K/AKT/mTOR pathway is considered to be a central regulatory pathway of protein translation during cell proliferation, growth, differentiation, and survival (38,39). The dysregulation of the mTOR signaling pathway, presented in many type of tumors including gliomas (40)(41)(42)(43), may represent a signaling schema that responds to virus infection in a proapoptotic manner through the integration of many different signals (22,44). Upon activation, mTOR phosphorylates its downstream targets, such as p70S6K, promoting cell survival through phosphorylation (inactivation) of the proapoptotic protein BAD (45).…”

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confidence: 99%

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Oncolytic adenoviral vectors which employ the survivin promoter induce glioma oncolysis via a process of beclin-dependent autophagy

et al. 2009

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Abstract. Survivin has gained attention as a tumor-specific marker which is upregulated in a variety of neoplasms. Although the survivin protein is implicated in anti-apoptotic tumor pathways, little is known about the function of the survivin promoter. In this study, we constructed a conditionally replicative adenoviral vector (CRAd) that utilizes the survivin promoter and examined the mechanism of CRAd induced cell death in malignant glioma. Our results indicate that CRAd vectors which utilize the survivin promoter effectively replicate in glioma cells and exhibit a high oncolytic effect. The survivin-mediated CRAd appeared to induce apoptosis as measured by Annexin/7-AAD. Caspase-3 and BAX mRNAs were upregulated based on microarray data, however, Western blot analysis of infected cells showed no evidence of elevated caspase-3, BAX, or p53 protein expression. Of note, at each time point infected glioma cells showed no evidence of activated BAD or AKT. The inhibition of AKT signaling led us to examine autophagy in infected cells. Electron micrographs of virally infected glioma cells suggested autophagosomal-mediated cell death and selective blocking of beclin with siRNA prevented autophagy. These results indicate that the survivin promoter enhances viral replication and induces autophagy of infected glioma cells via a beclindependent mechanism.

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Section: Introductionmentioning

confidence: 91%

Section: Cell Cycle Analysismentioning

confidence: 99%

mentioning

confidence: 99%

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Oncolytic adenoviral vectors which employ the survivin promoter induce glioma oncolysis via a process of beclin-dependent autophagy

et al. 2009

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“…However, there are only two reports showing that virus-induced ecto-CRT was correlated with enhanced intratumoral infiltrations of immune subpopulations, which accounted for the 'in vivo' remarkable antitumor immunity. 9,65 Several studies showed that recombinant oncolytic adenoviruses induced ACD in human malignant glioma cells, 120 brain tumor stem cells, 121 osteosarcoma cells, 105 and lung cancer cells. 122 Newcastle disease virus also triggered autophagy in glioma cells to promote its viral replication.…”

Section: Different Types Of Immunogenic Cancer Cell Death H Inoue Andmentioning

confidence: 99%

Multimodal immunogenic cancer cell death as a consequence of anticancer cytotoxic treatments

2013

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Apoptotic cell death generally characterized by a morphologically homogenous entity has been considered to be essentially non-immunogenic. However, apoptotic cancer cell death, also known as type 1 programmed cell death (PCD), was recently found to be immunogenic after treatment with several chemotherapeutic agents and oncolytic viruses through the emission of various danger-associated molecular patterns (DAMPs). Extensive studies have revealed that two different types of immunogenic cell death (ICD) inducers, recently classified by their distinct actions in endoplasmic reticulum (ER) stress, can reinitiate immune responses suppressed by the tumor microenvironment. Indeed, recent clinical studies have shown that several immunotherapeutic modalities including therapeutic cancer vaccines and oncolytic viruses, but not conventional chemotherapies, culminate in beneficial outcomes, probably because of their different mechanisms of ICD induction. Furthermore, interests in PCD of cancer cells have shifted from its classical form to novel forms involving autophagic cell death (ACD), programmed necrotic cell death (necroptosis), and pyroptosis, some of which entail immunogenicity after anticancer treatments. In this review, we provide a brief outline of the well-characterized DAMPs such as calreticulin (CRT) exposure, high-mobility group protein B1 (HMGB1), and adenosine triphosphate (ATP) release, which are induced by the morphologically distinct types of cell death. In the latter part, our review focuses on how emerging oncolytic viruses induce different forms of cell death and the combinations of oncolytic virotherapies with further immunomodulation by cyclophosphamide and other immunotherapeutic modalities foster dendritic cell (DC)-mediated induction of antitumor immunity. Accordingly, it is increasingly important to fully understand how and which ICD inducers cause multimodal ICD, which should aid the design of reasonably multifaceted anticancer modalities to maximize ICD-triggered antitumor immunity and eliminate residual or metastasized tumors while sparing autoimmune diseases.

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“…It is known that infection results in a rounded shape and condensation of the cytoplasm, that is, cytopathic effect (CPE). Apoptotic and necrotic mechanisms have been proposed and recent studies 14,15 suggest that Ad infected cancer cells feature autophagy, a form of programmed cell death distinct from apoptosis, characterized by the degradation of intracellular components via the lysosome. 16 Radiation alone has also been shown to induce autophagy.…”

Section: Uiccmentioning

confidence: 99%

Mre11 inhibition by oncolytic adenovirus associates with autophagy and underlies synergy with ionizing radiation

Rajecki

Hällström

Hakkarainen

et al. 2009

Intl Journal of Cancer

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New treatment approaches are needed for hormone refractory prostate cancer. Oncolytic adenoviruses are promising anti-cancer agents, and their efficacy can be improved by combining with conventional therapies such as ionizing radiation. The aim of this study was to determine the timing of oncolytic adenovirus treatment with regard to radiation and study the mechanisms of synergy in combination treatment. Prostate cancer cells were infected with oncolytic adenoviruses, irradiated and synergy mechanisms were assessed. In vivo models of combination treatment were tested. Radiation and oncolytic viruses were synergistic when viral infection was scheduled 24 hr after irradiation. Combination of oncolytic adenovirus with radiotherapy significantly increased antitumor efficacy in vivo compared to either agent alone. Microarray analysis showed dysregulated pathways including cell cycle, mTOR and antigen processing pathways. Functional analysis showed that adenoviral infection was accompanied with degradation of proteins involved in DNA break repair. Mre11 was degraded for subsequent inactivation of Chk2-Thr68 in combination treated cells, while cH2AX-Ser139 was elevated implicating the persistence of DNA double strand breaks. Increased autophagocytosis was seen in combination treated cells. Combination treatment did not increase apoptosis or virus replication. The results provide evidence of the antitumor efficacy of combining oncolytic adenoviruses with irradiation as a therapeutic strategy for the treatment of prostate cancer. Further, these findings propose a molecular mechanism that may be important in radiation induced cell death, autophagy and viral cytopathic effect. ' 2009 UICC

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Autophagic Cell Death of Malignant Glioma Cells Induced by a Conditionally Replicating Adenovirus

Abstract: hTERT-Ad may kill telomerase-positive cancer cells by inducing autophagic cell death.

Cited by 155 publications

References 53 publications

Oncolytic adenoviral vectors which employ the survivin promoter induce glioma oncolysis via a process of beclin-dependent autophagy

Oncolytic adenoviral vectors which employ the survivin promoter induce glioma oncolysis via a process of beclin-dependent autophagy

Multimodal immunogenic cancer cell death as a consequence of anticancer cytotoxic treatments

Mre11 inhibition by oncolytic adenovirus associates with autophagy and underlies synergy with ionizing radiation

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