title: Herpes simplex virus type 1 VP22-mediated intercellular delivery of PTEN increases the antitumor activity of PTEN in esophageal squamous cell carcinoma cells in vitro and in vivo.
abstract: In the past decade, studies have revealed that the phosphatase and tensin homolog (PTEN) protein, a tumor suppressor, comprises a potential biological marker and therapeutic target for esophageal squamous cell carcinoma (ESCC). As such, the delivery of the PTEN gene represents a powerful strategy for ESCC therapy. The tegument protein VP22 of herpes simplex virus type 1 (HSV-1) has been reported to act as a transporter of heterologous proteins across the host cell membrane, thereby enhancing the biological functions of these proteins. In the present study, the intercellular delivery and antitumor activity of the fusion protein PTEN-VP22 were examined in the esophageal squamous cell carcinoma cell line Eca109 both in vitro and in vivo. VP22-mediated PTEN intercellular delivery was confirmed in the Eca109 cells by western blot analysis and by quantitation of immunofluorescence. VP22 alone did not exert antiproliferative effects or induce cell cycle arrest, induction of apoptosis, blockage of the Akt and focal adhesion kinase (FAK) pathways, tumor growth inhibition, or antiangiogenic effects in Eca109 cells. However, compared with PTEN alone, PTEN-VP22 exerted significantly higher antiproliferative effects and induced cell cycle arrest at G1 stage, apoptosis and antiangiogenic effects in Eca109 cells. Together, our findings demonstrate that VP22 alone does not exert antitumor activity directly; however, this protein mediates the intercellular delivery of PTEN and thereby increases its intracellular concentration to achieve a therapeutic steady state, leading to an overall increase in the antitumor activity of PTEN. This study provides further experimental data to confirm the potential of VP22-based intercellular delivery strategies for enhancing the efficacy of gene therapy for cancer treatment.
authors.affiliation: Department of Pharmacy, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, P.R. China.
authors.forename: Xian
authors.initials: X
authors.lastname: Yu
authors.affiliation: Institute of Materia Medica, North Sichuan Medical College, Nanchong, Sichuan 637007, P.R. China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Li
authors.affiliation: Department of Orthopaedics, Chongqing General Hospital, Chongqing 400014, P.R. China.
authors.forename: Yifan
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Institute of Materia Medica, North Sichuan Medical College, Nanchong, Sichuan 637007, P.R. China.
authors.forename: Jun
authors.initials: J
authors.lastname: Lei
authors.affiliation: Institute of Materia Medica, North Sichuan Medical College, Nanchong, Sichuan 637007, P.R. China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Institute of Materia Medica, North Sichuan Medical College, Nanchong, Sichuan 637007, P.R. China.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004337:Drug Carriers / Q000494:pharmacology*; D004938:Esophageal Neoplasms / Q000188:drug therapy*; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D006801:Humans; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D051059:PTEN Phosphohydrolase / Q000494:pharmacology*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D015678:Viral Structural Proteins / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D011993:Recombinant Fusion Proteins; D015678:Viral Structural Proteins; C073413:herpes simplex virus type 1 protein VP22; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase