Spontaneous and controllable activation of suicide gene expression driven by the stress-inducible grp78 promoter resulting in eradication of sizable human tumors.
GRP78 is a stress-inducible chaperone protein with antiapoptotic properties that is overexpressed in transformed cells and cells under glucose starvation, acidosis, and hypoxic conditions that persist in poorly vascularized tumors. Previously we demonstrated that the Grp78 promoter is able to eradicate tumors using murine cells in immunocompetent models by driving expression of the HSV-tk suicide gene. Here, through the use of positron emission tomography (PET) imaging, we provide direct evidence of spontaneous in vivo activation of the HSV-tk suicide gene driven by the Grp78 promoter in growing tumors and its activation by photodynamic therapy (PDT) in a controlled manner. In this report, we evaluated whether this promoter can be applied to human cancer therapy. We observed that the Grp78 promoter, in the context of a retroviral vector, was highly activated by stress and PDT in three different types of human breast carcinomas independent of estrogen receptor and p53. Complete regression of sizable human tumors was observed after prodrug ganciclovir treatment of the xenografts in immunodeficient mice. In addition, the Grp78 promoter-driven suicide gene is strongly expressed in a variety of human tumors, including human osteosarcoma. In contrast, the activity of the murine leukemia virus (MuLV) long-terminal repeat (LTR) promoter varied greatly in different human breast carcinoma cell lines, and in some cases, stress resulted in partial suppression of the LTR promoter activity. In transgenic mouse models, the Grp78 promoter-driven transgene is largely quiescent in major adult organs but highly active in cancer cells and cancer-associated macrophages, which can diffuse to tumor necrotic sites devoid of vascular supply and facilitate cell-based therapy. Thus, transcriptional control through the use of the Grp78 promoter offers multiple novel approaches for human cancer gene therapy.
Dong
Dezheng
D
Department of Biochemistry and Molecular Biology, University of Southern California Keck School of Medicine, 1441 Eastlake Avenue, Los Angeles, CA 90089-9176, USA.
Dubeau
Louis
L
Bading
James
J
Nguyen
Khoi
K
Luna
Marian
M
Yu
Hong
H
Gazit-Bornstein
Gadi
G
Gordon
Erlinda M
EM
Gomer
Charles
C
Hall
Frederick L
FL
Gambhir
Sanjiv S
SS
Lee
Amy S
AS
D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D015774:Ganciclovir / Q000627:therapeutic use; D015870:Gene Expression; D041722:Genes, Transgenic, Suicide / Q000235:genetics*; D015316:Genetic Therapy; D005947:Glucose / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D009052:Leukemia Virus, Murine / Q000235:genetics; D015674:Mammary Neoplasms, Animal / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008819:Mice, Nude; D018832:Molecular Chaperones / Q000235:genetics* / Q000378:metabolism; D012516:Osteosarcoma / Q000473:pathology / Q000628:therapy*; D010778:Photochemotherapy; D049268:Positron-Emission Tomography; D011401:Promoter Regions, Genetic / Q000187:drug effects*; D011960:Receptors, Estrogen / Q000378:metabolism; D018139:Simplexvirus / Q000235:genetics; D013312:Stress, Physiological; D013937:Thymidine Kinase / Q000235:genetics*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000998:Antiviral Agents; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D018832:Molecular Chaperones; D011960:Receptors, Estrogen; D016159:Tumor Suppressor Protein p53; D013937:Thymidine Kinase; D005947:Glucose; D015774:Ganciclovir