Jianxiang Wang

University of Texas MD Anderson Cancer Center, Houston, TX, United States

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Publications (9)50.28 Total impact

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    ABSTRACT: GLIPR1 is a p53 target gene known to be downregulated in prostate cancer, and increased endogenous GLIPR1 expression has been associated with increased production of reactive oxygen species, increased apoptosis, decreased c-Myc protein levels and increased cell cycle arrest. Recently, we found that upregulation of GLIPR1 in prostate cancer cells increases mitotic catastrophe through interaction with heat shock cognate protein 70 (Hsc70) and downregulation of Aurora kinase A and TPX2. In this study, we evaluated the mechanisms of recombinant GLIPR1 protein (glioma pathogenesis-related protein 1-transmembrane domain deleted [GLIPR1-ΔTM]) uptake by prostate cancer cells and the efficacy of systemic GLIPR1-ΔTM administration in a prostate cancer xenograft mouse model. GLIPR1-ΔTM was selectively internalized by prostate cancer cells, leading to increased apoptosis through reactive oxygen species production and to decreased c-Myc protein levels. Interestingly, GLIPR1-ΔTM was internalized through clathrin-mediated endocytosis in association with Hsc70. Systemic administration of GLIPR1-ΔTM significantly inhibited VCaP xenograft growth. GLIPR1-ΔTM showed no evidence of toxicity following elimination from mouse models 8 hr after injection. Our results demonstrate that GLIPR1-ΔTM is selectively endocytosed by prostate cancer cells, leading to increased reactive oxygen species production and apoptosis, and that systemic GLIPR1-ΔTM significantly inhibits growth of VCaP xenografts without substantial toxicity.
    International Journal of Cancer 04/2014; 134(8):2003-13. · 6.20 Impact Factor
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    ABSTRACT: OBJECTIVES: The objectives of this study are to explore the potential benefits of combining AdGlipr1 (or AdGLIPR1) gene therapy with radiotherapy using subcutaneous prostate and bladder cancer models. MATERIALS AND METHODS: Combination adenoviral vector-mediated gene therapy and radiotherapy were applied to 178-2 BMA and TSU-Pr1 cells in vitro and colony formation and apoptosis were analyzed. In addition, combination therapies were administered to mice bearing subcutaneous 178-2 BMA and TSU-Pr1 tumors, and tumor growth suppression and survival extension were compared with the monotherapies (AdGlipr1/AdGLIPR1 and radiotherapy) or control vector Adv/CMV/βgal, as well as single-cycle treatment with 2-cycle treatment. RESULTS: Combination treatment significantly suppressed colony formation and increased apoptosis in vitro. In vivo, combination therapy produced significant 178-2 BMA and TSU-Pr1 tumor growth suppression and survival extension compared with the monotherapies or the control. Further tumor growth suppression and survival extension were observed after 2 cycles of the combination treatment. CONCLUSIONS: Combining AdGlipr1 (AdGLIPR1) with radiotherapy may achieve additive or synergistic tumor control in selected prostate and bladder tumors, and additional therapeutic effects may result with repeated treatment cycles.
    Urologic Oncology 02/2013; · 3.65 Impact Factor
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    ABSTRACT: Caveolin 1 (Cav-1) is a plasma membrane-associated protein with the capacity to modulate signaling activities in a context-dependent fashion. Interactions between Cav-1 and low-density lipoprotein receptor-related protein 6 (LRP6) were reported to be important for the regulation of Wnt-β-catenin (β-cat) signaling. Cav-1 also interacts with insulin and IGF-I receptors (IGF-IR/IR) and can stimulate IR kinase activities. We found positive correlation between Cav-1 and LRP6 expression in both human primary prostate cancer and metastasis tissues and in PC-3 cells. Cav-1 stimulation of Wnt-β-cat signaling and c-Myc levels was positively associated with LRP6 expression in LNCaP, PC-3, and DU145 prostate cancer cells. Importantly, LRP6 and, to a lesser extent, Cav-1 were found to stimulate aerobic glycolysis. These activities were positively associated with the expression of HK2 and Glut3 and shown to be dependent on Akt signaling by both gene knockdown and chemical inhibition methods. We further showed that Cav-1 and LRP6 exert their effects on Akt and glycolytic activities by stimulating IGF-IR/IR signaling. Overall, our results demonstrate that Cav-1 interacts with LRP6 to generate an integrated signaling module that leads to the activation of IGF-IR/IR and results in stimulation of Akt- mTORC1 signaling and aerobic glycolysis in prostate cancer.
    Cancer Research 01/2013; · 8.65 Impact Factor
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    ABSTRACT: In this study we report that expression of glioma pathogenesis-related protein 1 (GLIPR1) regulated numerous apoptotic, cell cycle, and spindle/centrosome assembly-related genes, including AURKA and TPX2, and induced apoptosis and/or mitotic catastrophe (MC) in prostate cancer (PCa) cells, including p53-mutated/deleted, androgen-insensitive metastatic PCa cells. Mechanistically, GLIPR1 interacts with heat shock cognate protein 70 (Hsc70); this interaction is associated with SP1 and c-Myb destabilization and suppression of SP1- and c-Myb-mediated AURKA and TPX2 transcription. Inhibition of AURKA and TPX2 using siRNA mimicked enforced GLIPR1 expression in the induction of apoptosis and MC. Recombinant GLIPR1-ΔTM protein inhibited AURKA and TPX2 expression, induced apoptosis and MC, and suppressed orthotopic xenograft tumor growth. Our results define a novel GLIPR1-regulated signaling pathway that controls apoptosis and/or mitotic catastrophe in PCa cells and establishes the potential of this pathway for targeted therapies.
    Molecular oncology 12/2012; · 6.70 Impact Factor
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    ABSTRACT: Prostate cancer is characterized by extreme heterogeneity and multifocality of the primary tumour. The available clinical, pathological and molecular data suggest a lack of substantial clonal expansion at the primary site, yet metastatic progression of the disease often proceeds in an unpredictable and clinically undetectable fashion. Clinical and experimental data suggest that primary prostate cancer tumour cells can seed from relatively small tumour foci at the primary site. Overall, this unique biological pattern of progression presents unique and challenging problems regarding the detection and treatment of the disease. In general, currently used potentially curative therapies involve a single cytoablative modality (radical prostatectomy or radiation therapy) and are exclusively directed at the malignant cells within the prostate gland. At present the widespread use of these treatments has not resulted in substantial reduction in mortality from prostate cancer. Gene therapy used alone or as an adjuvant approach could, at least conceptually, provide a rational solution for the prostate cancer dilemma. With gene therapy protocols designed to stimulate antitumour immunity, it may be possible to treat localized and systemic disease effectively and simultaneously. Our previous preclinical and clinical studies have focused on the use of adenoviral vector-mediated HSV-tk+GCV (Herpes Simplex Virus thymidine kinase + ganciclovir) in situ gene therapy for prostate cancer. More recently, specific immunomodulatory genes, such as interleukin-12 (IL-12), have been tested using adenoviral vector-mediated in situ and gene-modified cell based vaccine protocols. The results of these preclinical studies are promising and demonstrate the possibility of effectively generating cytotoxic activities in localized prostate cancers through the recruitment of activated immunocytes while generating systemic anti-tumour immunity that results in antimetastatic activities. We discuss the potential of IL-12 gene therapy for prostate cancer in this review.
    11/2006: pages 79-91;
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    ABSTRACT: Introduction: We previously documented that adenoviral vector-mediated murine RTVP-1 (AdmRTVP-1) gene therapy significantly suppresses the growth of mouse prostate cancer through direct cytotoxicity and the induction of a systemic anti-tumor immune response. This study explores the potential benefits of combining AdmRTVP-1 or adenoviral vector-mediated human RTVP-1 (AdhRTVP-1) gene therapy with irradiation (XRT) to enhance therapeutic efficacy in a subcutaneous prostate cancer model.Methods: The therapeutic effects of AdmRTVP-1 or AdhRTVP-1 alone or in combination with XRT were evaluated in vitro and in vivo. Tumors were established in 129/Sv adult male mice by subcutaneous inoculation of 5 × 104 178-2 BMA mouse prostate cancer cells. Xenograft tumors were established in athymic nude mice by subcutaneous inoculation of 5 × 106 TSU-Pr1 human prostate cancer cells. The AdmRTVP-1 dose was determined by dose escalation studies using doses from 5 × 107 to 5 × 108 PFU, and the AdhRTVP-1 dose was 5 × 108 PFU. Radiation was administered as a single dose of 5Gy 48hrs after vector injection. Tumor size was monitored every other day and tumor wet weight was determined fourteen days after vector injection. In separate studies, animals with subcutaneous tumors were treated and evaluated for survival benefit.Results: AdmRTVP-1 or AdhRTVP-1 and XRT demonstrated combinatorial effects in vitro as determined by colony formation assay, DAPI staining or FACS analysis of apoptosis. In vivo the optimal dose of AdmRTVP-1 for growth suppression of subcutaneous 178-2 BMA tumors was 5 × 108 PFU. In this model the combination of AdmRTVP-1 + XRT produced statistically significant tumor growth suppression compared to therapy with AdmRTVP-1 alone, control vector Adv/CMV/bgal, or Adv/CMV/bgal + XRT (P < 0.0001, P < 0.0001, P < 0.0001, respectively). In addition significant prolongation in survival to 27.7 days was demonstrated for the combination of AdmRTVP1 + XRT compared with Adv/CMV/bgal (18.1 days, P < 0.0001), Adv/CMV/bgal + XRT (19.4 days, P < 0.0001) or AdmRTVP1 alone (23.6 days, P=0.0350). Xenograft experiments revealed that the combination of AdhRTVP1 + XRT produced statistically significant tumor growth suppression compared to therapy with AdhRTVP-1 alone, control vector Adv/CMV/bgal, or Adv/CMV/bgal + XRT (P < 0.0001, P < 0.0001, P < 0.0001, respectively). Significant prolongation in survival to 132 days was also demonstrated for the combination of AdhRTVP-1 + XRT compared with Adv/CMV/bgal (70 days, P = 0.0042), AdhRTVP-1 alone (80.7 days, P = 0.0245) or Adv/CMV/bgal + XRT (101.2 days, P = 0.0625).Conclusions: Combination in situ AdmRTVP-1 or AdhRTVP-1 gene therapy + XRT significantly suppresses tumor growth and prolongs survival compared to gene or XRT therapy alone. Future studies will be directed at investigating the mechanism of the combined therapeutic effect of AdRTVP-1 gene therapy + XRT.
    Molecular Therapy 01/2004; 9. · 7.04 Impact Factor
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    ABSTRACT: We investigated the efficacy of intratumoral injection of macrophages transduced with murine IL-12 recombinant adenoviral vector (AdmIL-12) using the orthotopic 178-2 BMA mouse prostate cancer model. AdmIL-12-transduced macrophages secreted IL-12 in vitro and demonstrated increased surface expression of MHC classes I and II as well as F4/80 antigen compared with uninfected macrophages or those infected with an adenoviral vector containing beta-galactosidase (Adbetagal) in control macrophages. AdmIL-12-transduced macrophages injected into orthotopic 178-2 BMA tumors in vivo induced significant suppression of primary tumor growth and spontaneous lung metastases compared with controls. These antitumor and antimetastatic effects were comparable with those resulting from direct orthotopic delivery of the AdmIL-12 vector. Mice with orthotopic tumors treated with AdmIL-12-transduced macrophages survived significantly longer than controls. Analysis of tumors demonstrated significantly increased infiltration of CD4+ and CD8+ T cells in those injected with AdmIL-12-transduced macrophages compared with controls. Splenocyte-derived cytotoxic natural killer cell activity was enhanced on day 2 after AdmIL-12-transduced macrophage injection, and on day 14, tumor-specific T-lymphocyte activities were increased compared with control, Adbetagal-infected macrophages. Trafficking studies confirmed that intratumorally injected, AdmIL-12-transduced macrophages could migrate to draining lymph nodes. Overall, this novel approach to prostate cancer therapy demonstrates antitumor immune responses that provide effective antimetastatic activities in preclinical studies.
    Cancer Research 12/2003; 63(22):7853-60. · 8.65 Impact Factor
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    ABSTRACT: We previously identified the mouse RTVP-1 (mRTVP-1; related to testes-specific, vespid, and pathogenesis proteins) gene as a direct target of p53 with proapoptotic activities in various cancer cell lines, including prostate cancer. To test the therapeutic potential of mRTVP-1 we constructed an adenoviral vector capable of efficient transduction and expression of mRTVP-1 (AdmRTVP-1) and used this vector in an orthotopic, metastatic mouse model of prostate cancer. A single intratumoral administration of AdmRTVP-1 gene therapy significantly reduced primary tumor wet weight compared with control Adbetagal-injected tumors at two time points after injection with two different vector doses (p < or = 0.01 at 7 and 14 days). Spontaneous metastasis to lung was also significantly reduced (p < or = 0.02). Evaluation of treated tumors revealed increased apoptosis and lower microvessel density counts. In a rat aortic ring sprouting assay, AdmRTVP-1 inhibited endothelial cell sprouting compared with Adbetagal, confirming its antiangiogenic activity. These therapeutic activities were associated with a significant increase in survival from 22.9 to 26.8 days (p = 0.003) in this aggressive model of prostate cancer. Interestingly, there were significant increases in the infiltration of tumor-associated macrophages, dendritic cells, and CD8+ T cells, which persisted at 14 days posttreatment in the AdmRTVP-1-treated tumors compared with Adbetagal control-treated tumors. In addition, significantly increased natural killer and cytotoxic T lymphocyte activities were demonstrated in the mice with AdmRTVP-1-treated tumors. The unique therapeutic properties of AdmRTVP-1 gene therapy demonstrated in this study provide new opportunities for gene and immunotherapy of prostate cancer and potentially other malignancies.
    Human Gene Therapy 01/2003; 14(2):91-101. · 4.02 Impact Factor
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    ABSTRACT: We identified a novel mouse gene, mRTVP-1, as a p53 target gene using differential display PCR and extensive promoter analysis. The mRTVP-1 protein has 255 amino acids and differs from the human RTVP-1 (hRTVP-1) protein by two short in-frame deletions of two and nine amino acids. RTVP-1 mRNA was induced in multiple cancer cell lines by adenovirus-mediated delivery of p53 and by gamma irradiation or doxorubicin both in the presence and in the absence of endogenous p53. Analysis of RTVP-1 expression in nontransformed and transformed cells further supported p53-independent gene regulation. Using luciferase reporter and electrophoretic mobility shift assays we identified a p53 binding site within intron 1 of the mRTVP-1 gene. Overexpression of mRTVP-1 or hRTVP-1 induced apoptosis in multiple cancer cell lines including prostate cancer cell lines 148-1PA, 178-2BMA, PC-3, TSU-Pr1, and LNCaP, a human lung cancer cell line, H1299, and two isogenic human colon cancer cell lines, HCT116 p53(+/+) and HCT116 p53(-/-), as demonstrated by annexin V positivity, phase-contrast microscopy, and in selected cases 4',6'-diamidino-2-phenylindole staining and DNA fragmentation. Deletion of the signal peptide from the N terminus of RTVP-1 reduced its apoptotic activities, suggesting that a secreted and soluble form of RTVP-1 may mediate, in part, its proapoptotic activities.
    Molecular and Cellular Biology 06/2002; 22(10):3345-57. · 5.37 Impact Factor

Publication Stats

100 Citations
50.28 Total Impact Points

Institutions

  • 2012–2013
    • University of Texas MD Anderson Cancer Center
      • Genitourinary Medical Oncology
      Houston, TX, United States
  • 2002–2013
    • Baylor College of Medicine
      • Department of Urology
      Houston, Texas, United States