Inhibition of the multidrug-resistant phenotype by targeting YB-1 with a conditionally oncolytic adenovirus: implications for combinatorial treatment regimen with chemotherapeutic agents.
Bearing in mind the limited success of available treatment modalities for the therapy of multidrug-resistant tumor cells, alternative and complementary strategies need to be developed. It is known that the transcriptional activation of genes, such as MDR1 and MRP1, which play a major role in the development of a multidrug-resistant phenotype in tumor cells, involves the Y-box protein YB-1. Thus, YB-1 is a promising target for new therapeutic approaches to defeat multidrug resistance. In addition, it has been reported previously that YB-1 is an important factor in adenoviral replication because it activates transcription from the adenoviral E2-late promoter. Here, we report that an oncolytic adenovirus, named Xvir03, expressing the viral proteins E1B55k and E4orf6, leads to nuclear translocation of YB-1 and in consequence to viral replication and cell lysis in vitro and in vivo. Moreover, we show that Xvir03 down-regulates the expression of MDR1 and MRP1, indicating that recruiting YB-1 to the adenoviral E2-late promoter for viral replication is responsible for this effect. Thus, nuclear translocation of YB-1 by Xvir03 leads to resensitization of tumor cells to cytotoxic drugs. These data reveal a link between chemotherapy and virotherapy based on the cellular transcription factor YB-1 and provide the basis for formulating a model for a novel combined therapy regimen named Mutually Synergistic Therapy.
Mantwill
Klaus
K
Institute of Experimental Oncology and Department of Urology, Technical University of Munich, Klinikum rechts der Isar, Germany. klaus.mantwill@web.de
Köhler-Vargas
Nadia
N
Bernshausen
Alexandra
A
Bieler
Alexa
A
Lage
Hermann
H
Kaszubiak
Alexander
A
Surowiak
Pavel
P
Dravits
Tanja
T
Treiber
Uwe
U
Hartung
Rudolf
R
Gansbacher
Bernd
B
Holm
Per S
PS
D000256:Adenoviridae / Q000235:genetics / Q000502:physiology*; D017502:Adenovirus E2 Proteins / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002467:Cell Nucleus / Q000378:metabolism; D003131:Combined Modality Therapy; D004268:DNA-Binding Proteins / Q000378:metabolism*; D003630:Daunorubicin / Q000494:pharmacology; D000077143:Docetaxel; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D019450:Genes, MDR / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000096:biosynthesis / Q000235:genetics*; D009687:Nuclear Proteins; D050130:Oncolytic Virotherapy / Q000379:methods*; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000628:therapy* / Q000821:virology; D043823:Taxoids / Q000494:pharmacology; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays; D051840:Y-Box-Binding Protein 1
D017502:Adenovirus E2 Proteins; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D003630:Daunorubicin; D000077143:Docetaxel; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009687:Nuclear Proteins; D043823:Taxoids; D051840:Y-Box-Binding Protein 1; C070856:YBX1 protein, human; C421109:multidrug resistance-associated protein 1