SMAD4: a predictive marker of PDAC cell permissiveness for oncolytic infection with parvovirus H-1PV.
Pancreatic ductal adenocarcinoma (PDAC) represents the eighth frequent solid tumor and fourth leading cause of cancer death. Because current treatments against PDAC are still unsatisfactory, new anticancer strategies are required, including oncolytic viruses. Among these, autonomous parvoviruses (PV), like MVMp (minute virus of mice) and H-1PV are being explored as candidates for cancer gene therapy. Human PDAC cell lines were identified to display various susceptibilities to an infection with H-1PV. The correlation between the integrity of the transcription factor SMAD4, mutated in 50% of all PDAC, and H-1PV permissiveness was particularly striking. Indeed, mutation or deletion of SMAD4 dramatically reduced the activity of the P4 promoter and, consequently, the accumulation of the pivotal NS1 protein. By means of DNA affinity immunoblotting, novel binding sites for SMAD4 and c-JUN transcription factors could be identified in the P4 promoter of H-1PV. The overexpression of wild-type SMAD4 in deficient cell lines (AsPC-1, Capan-1) stimulated the activity of the P4 promoter, whereas interference of endogenous SMAD4 function with a dominant-negative mutant decreased the viral promoter activity in wild-type SMAD4-expressing cells (Panc-1, MiaPaCa-2) reducing progeny virus production. In conclusion, the importance of members of the SMAD family for H-1PV early promoter P4 activity should guide us to select SMAD4-positive PDACs, which may be possible targets for an H-1PV-based cancer therapy.
Dempe
Sebastian
S
Abt F010, Infection and Cancer Program, Tumor Virology Division, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 242, Heidelberg, Germany
Stroh-Dege
Alexandra Y
AY
Schwarz
Elisabeth
E
Rommelaere
Jean
J
Dinsart
Christiane
C
D000230:Adenocarcinoma / Q000235:genetics / Q000556:secondary / Q000821:virology*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000556:secondary / Q000821:virology*; D015972:Gene Expression Regulation, Neoplastic; D005822:Genetic Vectors; D052661:H-1 parvovirus / Q000502:physiology*; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000473:pathology / Q000821:virology*; D010322:Parvoviridae Infections / Q000235:genetics / Q000473:pathology / Q000821:virology*; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051901:Smad4 Protein / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication
D014408:Biomarkers, Tumor; C106202:NS1 protein, parvovirus; D012333:RNA, Messenger; D051901:Smad4 Protein; D017361:Viral Nonstructural Proteins; D008156:Luciferases