Oncolysis of pancreatic tumour cells by a gamma34.5-deleted HSV-1 does not rely upon Ras-activation, but on the PI 3-kinase pathway.
The ability of viruses to selectively target, replicate within, and destroy tumour cells without deleterious effects in normal cells (oncolysis), makes the use of viruses as an attractive tool for cancer treatment. Pancreatic adenocarcinoma, being insensitive to traditional therapy and having a rather poor prognosis, represents a suitable target to evaluate viral oncolysis as a novel therapeutic approach. Herpes simplex virus (HSV) has been reported to produce an oncolytic effect in cells overexpressing Ras. As Ras signalling is frequently aberrant in pancreatic cancer, we compared four pancreatic cell lines (which differ in the presence of mutated or wild-type ras) for their ability to support growth of gamma34.5-replication attenuated HSV-1 (R3616). Our data show that permissiveness to viral replication is neither associated with enhanced Ras signalling nor with defective PKR activity. By contrast, we provide evidence that disregulation of the PI 3-kinase signalling pathway allows conditionally replication-defective R3616 virus to overcome the cellular antiviral activity.
Sarinella
F
F
Department of Histology, Microbiology and Medical Biotechnologies, Section of Microbiology and Virology, Medical School, University of Padua, Padua, Italy.
Calistri
A
A
Sette
P
P
Palù
G
G
Parolin
C
C
D000230:Adenocarcinoma / Q000201:enzymology / Q000628:therapy* / Q000821:virology; D045744:Cell Line, Tumor; D002867:Chromones / Q000627:therapeutic use; D005419:Flavonoids / Q000627:therapeutic use; D017353:Gene Deletion; D011905:Genes, ras; D015316:Genetic Therapy / Q000379:methods*; D006561:Herpes Simplex / Q000150:complications; D018259:Herpesvirus 1, Human / Q000235:genetics*; D006801:Humans; D015151:Immunoblotting / Q000379:methods; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D009025:Morpholines / Q000627:therapeutic use; D050130:Oncolytic Virotherapy / Q000379:methods*; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000628:therapy* / Q000821:virology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015398:Signal Transduction; D014764:Viral Proteins / Q000235:genetics; D014779:Virus Replication / Q000235:genetics
D002867:Chromones; D005419:Flavonoids; D020929:Mitogen-Activated Protein Kinase Kinases; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D014764:Viral Proteins; C066469:gamma 34.5 protein, Human herpesvirus 1; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one