title: TAT-OSBP-1-MKK6(E), a novel TAT-fusion protein with high selectivity for human ovarian cancer, exhibits anti-tumor activity.
abstract: To improve the selectivity of TAT-fusion proteins for targeted cancer therapy, we developed a novel TAT-based target-specific fusion protein, TAT-OSBP-1-MKK6(E), and evaluated its selectivity and anti-tumor activity in vitro and in vivo. The fusion protein containing TAT-OSBP-1-MKK6(E) has three functional domains: (1) the protein transduction domain of TAT, (2) the human ovarian cancer HO8910 cell-specific binding peptide (OSBP-1) and (3) the potential anti-tumor effector domain of MKK6(E). The transduction efficiency, selectivity, cytotoxicity and apoptotic effect of TAT-OSBP-1-MKK6(E) were examined using immunofluorescence, CCK8 assay and flow cytometry. The in vivo anti-tumor efficacy and target specificity of the fusion protein were evaluated using a nude mouse model with subcutaneous xenografts of human ovarian cancer HO8910 cells. Tumor-bearing mice were divided into three treatment groups that received tail vein injections of TAT-OSBP-1-MKK6(E), TAT-OSBP-1 or normal saline. Tumor growth inhibition was determined by tumor volume, weight and morphology. The distribution and apoptotic effect of TAT-OSBP-1-MKK6(E) were assessed by immunohistochemical staining and TUNEL assays. TAT-OSBP-1-MKK6(E) can be selectively internalized into human ovarian cancer HO8910 cells, rather than normal ovarian OSE cells. In vivo, the fusion protein was mainly expressed in the tumor xenograft, but not in ovary or liver tissues. As a result, TAT-OSBP-1-MKK6(E) significantly induced growth inhibition and apoptosis of tumor cells in vitro and in vivo, with limited effects in normal cells and tissues. TAT-OSBP-1-MKK6(E) treatment can selectively target HO8910 cells in vitro and in vivo, leading to growth inhibition and apoptosis of tumor cells. As such, TAT-OSBP-1-MKK6(E) may be a potential approach for ovarian cancer target therapy.
authors.affiliation: Department of Obstetrics and Gynecology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, 510180, People's Republic of China.
authors.forename: Jiali
authors.initials: J
authors.lastname: Zhong
authors.forename: Jiali
authors.initials: J
authors.lastname: Kang
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Wang
authors.forename: Wenyan
authors.initials: W
authors.lastname: Jiang
authors.forename: Hua
authors.initials: H
authors.lastname: Liao
authors.forename: Jin
authors.initials: J
authors.lastname: Yuan
mesh_terms: D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D015696:Gene Products, tat / Q000235:genetics / Q000378:metabolism*; D015316:Genetic Therapy; D006801:Humans; D048669:MAP Kinase Kinase 6 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000628:therapy*; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D000098825:Oxysterol Binding Proteins
chemical_list: D015696:Gene Products, tat; D011987:Receptors, Steroid; D011993:Recombinant Fusion Proteins; D000098825:Oxysterol Binding Proteins; D048669:MAP Kinase Kinase 6; C482566:MAP2K6 protein, human