VSV virotherapy improves chemotherapy by triggering apoptosis due to proteasomal degradation of Mcl-1.
Overexpression of myeloid cell leukemia 1 protein (Mcl-1), an anti-apoptotic B-cell lymphoma 2 (Bcl-2) family member, contributes to chemotherapy resistance of tumors. The short half-life of Mcl-1 makes it an interesting target for therapeutic agents that negatively interfere with cellular protein biosynthesis, such as oncolytic viruses. Vesicular Stomatitis Virus (VSV) has been established as the oncolytic virus that efficiently disrupts de novo protein biosynthesis of infected cells. Here, we show that after VSV infection, Mcl-1 protein levels rapidly declined, whereas the expression of other members of the Bcl-2 family remained unchanged. Mcl-1 elimination was a consequence of proteasomal degradation, as overexpression of a degradation-resistant Mcl-1 mutant restored Mcl-1 levels. Mcl-1 rescue inhibited apoptosis and thereby confirmed that Mcl-1 downregulation contributes to VSV-induced apoptosis. In vitro, VSV virotherapy in combination with chemotherapy revealed an enhanced therapeutic effect compared with the single treatments, which could be reverted by Mcl-1 rescue or RNA interference (RNAi)-mediated knockdown of pro-apoptotic Bax and Bak proteins. Finally, in a tumor mouse model, combinations of doxorubicin and VSV showed a superior therapeutic efficacy compared with VSV or doxorubicin alone. In summary, our data indicate that VSV virotherapy is an attractive strategy to overcome tumor resistance against conventional chemotherapy by elimination of Mcl-1.
Department of Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, Hannover, Germany.
P
P
Schache
E
E
Gürlevik
N
N
Strüver
N
N
Woller
N
N
Malek
L
L
Zender
M
M
Manns
T
T
Wirth
F
F
Kühnel
S
S
Kubicka
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001343:Autophagy / Q000187:drug effects / Q000502:physiology; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D003588:Cytopathogenic Effect, Viral; D015536:Down-Regulation / Q000235:genetics; D004317:Doxorubicin / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006207:Half-Life; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000378:metabolism; D050130:Oncolytic Virotherapy; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis* / Q000378:metabolism; D034622:RNA Interference; D014721:Vesicular stomatitis Indiana virus / Q000235:genetics / Q000254:growth & development / Q000502:physiology*; D014779:Virus Replication / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D004317:Doxorubicin; D053148:Caspase 3; D046988:Proteasome Endopeptidase Complex