Inhibition of the Multidrug-Resistant Phenotype by Targeting YB-1 with a Conditionally Oncolytic Adenovirus: Implications for Combinatorial Treatment Regimen with Chemotherapeutic Agents

Mantwill, Klaus; Köhler-Vargas, Nadia; Bernshausen, Alexandra; Bieler, Alexa; Lage, Hermann; Kaszubiak, Alexander; Surowiak, Paweł; Dravits, Tanja; Treiber, Uwe; Härtung, R.; Gänsbacher, Bernd; Holm, Per Sonne

doi:10.1158/0008-5472.can-05-2339

Cited by 43 publications

(33 citation statements)

References 48 publications

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“…Our identification of YB-1 as an ITAF leads us to examine these data further, and interestingly, many of the mRNAs present in this screen contain known IRESs, e.g., cyclin T1 (6), cyclin D1 (42), vascular endothelial growth factor (17), and fibroblast growth factor (48), suggesting that YB-1 could be an ITAF that is associated with mRNAs that have a role in cell proliferation (13). In agreement with this observation, the overexpression of YB-1 in tumors is associated with a resistance to chemotherapy (15,24) and poor prognosis (51). This suggests a model where under conditions of cell stress (including the exposure of cells to chemotherapeutic agents), there is a decrease in global translation rates (11).…”

Section: Discussionsupporting

confidence: 63%

Identification of Internal Ribosome Entry Segment (IRES)-trans-Acting Factors for the Myc Family of IRESs

Cobbold

Spriggs

Haines

et al. 2008

Molecular and Cellular Biology

114

108

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The proto-oncogenes c-, L-, and N-myc can all be translated by the alternative method of internal ribosome entry whereby the ribosome is recruited to a complex structural element (an internal ribosome entry segment [IRES]). Ribosome recruitment is dependent upon the presence of IRES-trans-acting factors (ITAFs) that act as RNA chaperones and allow the mRNA to attain the correct conformation for the interaction of the 40S subunit. One of the major challenges for researchers in this area is to determine whether there are groups of ITAFs that regulate the IRES-mediated translation of subsets of mRNAs. We have identified four proteins, termed GRSF-1 (G-rich RNA sequence binding factor 1), YB-1 (Y-box binding protein 1), PSF (polypyrimidine tract binding protein-associated splicing factor), and its binding partner, p54nrb, that bind to the myc family of IRESs. We show that these proteins positively regulate the translation of the Myc family of oncoproteins (c-, L-, and N-Myc) in vivo and in vitro. Interestingly, synthesis from the unrelated IRESs, BAG-1 and Apaf-1, was not affected by YB-1, GRSF-1, or PSF levels in vivo, suggesting that these three ITAFs are specific to the myc IRESs. Myc proteins play a role in cell proliferation; therefore, these results have important implications regarding the control of tumorigenesis.The proteins encoded by the myc gene family function as sequence-specific transcription factors that regulate target genes integral to the processes of cell proliferation, differentiation, and cell death (2, 9). Although many of the functions of the three major myc genes are overlapping, unique properties have been ascribed to individual Myc proteins. For example, each of the Myc proteins can restore the growth and proliferative defects of c-myc null fibroblasts and can promote apoptosis following growth factor deprivation (23,30). In addition, all three proteins can regulate known myc target genes (23). Unique roles for these proteins are supported by the following observations: during embryogenesis and in adult tissues, the expression patterns of c-, L-, and N-Myc are distinct (52); homozygous null c-or N-myc mice die early in development, whereas targeted disruption of both L-myc alleles is not lethal; and in some instances, L-myc displays distinct cell transformation and transcriptional properties (1, 38, 39).It is not surprising, given the role of the Myc family of proteins in proliferation and apoptosis, that the expression of these proteins is highly regulated at the levels of both transcription and translation. Indeed, deregulated Myc expression, through either of these mechanisms, has been associated with tumorigenesis (12,35,36,49,50).Previous studies have shown that the 5Ј untranslated regions (UTRs) of c-, L-, and N-myc encoded by exon 1 each contain a complex RNA structural element known as an internal ribosome entry segment (IRES). Consequently, synthesis of the Myc family proteins can occur by the process of internal ribosome entry (18,19,28,45). In this mechanism of translation initi...

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Section: Discussionsupporting

confidence: 63%

Identification of Internal Ribosome Entry Segment (IRES)-trans-Acting Factors for the Myc Family of IRESs

Cobbold

Spriggs

Haines

et al. 2008

Molecular and Cellular Biology

114

108

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“…Especially, the sensitization to TMZ by YB-1 depletion, as recently shown by Gao et al, 41 could also be a main mechanism in our studies, when YB-1 is not at disposal because of viral replication. 42 It is established that VEGF plays an important role in tumor growth and thus is an accepted target for cancer therapy. 43 The adenovirus E1A protein is a multifunctional protein which amongst others has been shown to possess the ability to down regulate VEGF expression.…”

Section: Discussionmentioning

confidence: 99%

YB‐1 dependent virotherapy in combination with temozolomide as a multimodal therapy approach to eradicate malignant glioma

Holzmüller

Mantwill

Haczek

et al. 2011

Intl Journal of Cancer

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The human Y-box binding protein 1 (YB-1) is known to be a promising target for cancer therapy. We have demonstrated that YB-1 plays an important role in the adenoviral life cycle by regulating the adenoviral E2-gene expression. Thus, we studied the oncolytic effect of the recombinant adenovirus Ad-Delo3-RGD, in which the transactivation domain CR3 of the E1A protein is ablated to enable viral replication only in YB-1 positive cancer cells. In vitro Southern Blot analysis and cytopathic effect assays demonstrate high anti-glioma potency, which was significantly increased in combination with temozolomide (TMZ), daunorubicin and cisplatin. Since vascular endothelial growth factor (VEGF) is thought to promote the hypervascular phenotype of primary, malignant brain tumors, we also tested Ad-Delo3-RGD in regard to the inhibition of VEGF expression. Indeed, we found that Ad-Delo3-RGD induced VEGF down regulation, which was even amplified under hypoxic conditions. Tumor-bearing nudemice treated with the YB-1 dependent oncolytic adenovirus showed significantly smaller tumors than untreated controls. Furthermore, combination therapy with TMZ led to a regression in all treated animals with complete tumor regression in 33 % of analyzed mice, which was verified by bioluminescence imaging and histological studies. In addition, histopathological evaluation revealed enhanced apoptosis and a reduction in tumor vessel formation, indicating that AdDelo3-RGD has an anti-angiogenic effect in addition to its oncolytic capacity in vivo. Hence, our results demonstrate that the combination therapy of YB-1 dependent virotherapy and TMZ is effective in a xenograft glioma mouse model and might be useful in a YB-1 based clinical setting.

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“…The finding of Fujita et al, 29 who could show in breast cancer cells that YB-1 is translocated to the nucleus after paclitaxel treatment is in line with our hypothetic model termed Mutually Synergistic Therapy (MUST). 22 This may contribute to the enhanced oncolytic potential of AdDelo3-RGD in combination therapy too. However, it is still unknown, how YB-1 is translocated into the nucleus.…”

Section: Paclitaxel Combinationmentioning

confidence: 99%

Adenovirus-based virotherapy enabled by cellular YB-1 expression in vitro and in vivo

et al. 2009

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We have earlier described the oncolytic adenovirus vector dl520 that was rendered cancer-specific by deletion of the transactivation domain CR3 of the adenoviral E1A13S protein; this deletion causes antitumor activity in drug-resistant cells displaying nuclear YB-1 expression. We hypothesized that the anticancer activity of dl520 could be further improved by introducing the RGD motif in the fiber knob and by deletion of the adenoviral E1B19K protein (Ad-Delo3-RGD). In this study, the in vitro and in vivo antitumor activity of Ad-Delo3-RGD was investigated focussing on two pancreatic cancer cell lines MiaPaCa-2 and BxPC3 alone and in combination with cytotoxic drugs. Furthermore, luciferin-based bioluminescence imaging was established to study the therapeutic response in vivo. In addition, to confirm the specificity of Ad-Delo3-RGD for YB-1 a tetracycline-inducible anti-YB-1 shRNA-expressing cell variant EPG85-257RDB/tetR/YB-1 was used. This TetON regulatable expression system allows us to measure adenoviral replication by real-time PCR in the absence of YB-1 expression. The results confirmed the YB-1 dependency of Ad-Delo3-RGD and showed that Ad-Delo3-RGD has potent activity against human pancreatic cancer cells in vitro and in vivo, which was augmented by the addition of paclitaxel. However, although high replication capacity was measured in vitro and in vivo, complete tumor regression was not achieved, indicating the need for further improvements to treat pancreatic cancer effectively.

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Inhibition of the Multidrug-Resistant Phenotype by Targeting YB-1 with a Conditionally Oncolytic Adenovirus: Implications for Combinatorial Treatment Regimen with Chemotherapeutic Agents

Cited by 43 publications

References 48 publications

Identification of Internal Ribosome Entry Segment (IRES)-trans-Acting Factors for the Myc Family of IRESs

Identification of Internal Ribosome Entry Segment (IRES)-trans-Acting Factors for the Myc Family of IRESs

YB‐1 dependent virotherapy in combination with temozolomide as a multimodal therapy approach to eradicate malignant glioma

Adenovirus-based virotherapy enabled by cellular YB-1 expression in vitro and in vivo

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