Adenovirus-mediated REIC/Dkk-3 gene transfer inhibits tumor growth and metastasis in an orthotopic prostate cancer model

Edamura, Kohei; Nasu, Yasutomo; Takaishi, Mikiro; Kobayashi, Tomoko; Abarzúa, Fernando; Sakaguchi, Masakiyo; Kashiwakura, Yuji; Ebara, Shin; Sakaguchi, Takashi; Watanabe, Masami; Nh, Huh; Kumon, Hiromi

doi:10.1038/sj.cgt.7701071

Cited by 58 publications

(62 citation statements)

References 36 publications

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“…The suppression of tumor growth was further confirmed in an in vivo situation using an orthotopic tumor model. These phenomena were consistent with other published studies (3,5,9,10,(15)(16)(17)(18), showing that ectopic expression of REIC/ Dkk-3 induces apoptosis and inhibits cell proliferation in various cancer cells. Therefore, the lack or absence of endogenous REIC/Dkk-3 expression in RM9 cancer cells seems to be important for the cellular effects induced by the REIC/Dkk-3 overexpression.…”

Section: Discussionsupporting

confidence: 82%

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REIC/Dkk-3 stable transfection reduces the malignant phenotype of mouse prostate cancer RM9 cells

Chen

Watanabe²,

Huang³

et al. 2009

Int J Mol Med

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Abstract. The reduced expression in immortalized cells (REIC)/Dickkopf (Dkk)-3, a member of the Dkk gene family, is a tumor suppressor in a broad range of cancers. REIC/Dkk-3 transfected stable clones of mouse prostate cancer RM9 cells (RM9-REIC) and the empty vector-transfected control clone cells (RM9-EV) were established. Clones were used to evaluate the anti-cancer effects and a proteomics analysis of REIC/Dkk-3 continuous expression was performed. The RM9-REIC cells show a feeble appearance and the cell membrane shows irregular buds known as blebs. In vitro cell proliferation was significantly suppressed in RM9-REIC clones in comparison to the control. The apoptosis assay was done under standard culture conditions and RM9-REIC showed a higher incidence of apoptosis. The RM9-EV and RM9-REIC cells were orthotopically implanted into a C57BL/6 mouse prostate. After 2 weeks, the tumor growth was significantly inhibited in RM9-REIC cells in comparison to the control. Two-dimensional gel electrophoresis was used to examine the modification of protein expression by the gene transfection. The analysis with mass spectrometry disclosed that expression of peroxiredoxin-1, GST-P1, transgelin-2, MRP-L12, ARD, GRP78 and Sorcin were increased and eEF1A-1 and cyclophilin-40 protein were decreased in RM9-REIC cells. Therefore, REIC/Dkk-3 stable transfectants show a reduction of malignancy in mouse prostate cancer RM9 cells in vitro and in vivo. The result of the proteomics analysis might provide important clues to clarify the anti-cancer molecular mechanism of REIC/Dkk-3 gene transfer.

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Section: Discussionsupporting

confidence: 82%

“…There is accumulating evidence that the intracellular expression of REIC/Dkk-3 is negatively related to the development of a malignant and/or atypical cell phenotype (3,4,6,15,23,24). REIC/Dkk-3 overexpression in cancer cells inhibits the invasive and motile cell phenotype in vitro (23,24) and metastasis in vivo (15).…”

Section: Discussionmentioning

confidence: 99%

REIC/Dkk-3 stable transfection reduces the malignant phenotype of mouse prostate cancer RM9 cells

Chen

Watanabe²,

Huang³

et al. 2009

Int J Mol Med

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show abstract

“…Adenovirus mediated REIC/ Dkk-3 overexpression was previously demonstrated to induce significant apoptosis in injected tumor sites and robust antitumor effects (4)(5)(6)15). In vitro REIC/Dkk-3 overexpression by Ad-REIC in cancer cells resulted in plenty of REIC/Dkk-3 protein secretion into the culture media (data not shown).…”

Section: Overexpression Of Reic/dkk-3 Protein In Rm9 Orthotopicmentioning

confidence: 90%

“…In the other experiments shown in Fig. 4A, the orthotopic prostate cancer model with pre-established lung metastases was used (14,15) and the Ad-REIC or Ad-LacZ prepared as previously described (4) was injected into the orthotopic tumor on day 7. The injection of the agents was targeted to the center and periphery of each mass to deliver the agent diffusely and the tumor volume was determined as described previously (12).…”

Section: Preparation Of Recombinant Human Reic/dkk-3 Proteinmentioning

confidence: 99%

Immunological aspects of REIC/Dkk-3 in monocyte differentiation and tumor regression

Watanabe

Kashiwakura

Huang³

et al. 2009

Int J Oncol

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Abstract.The REIC/Dkk-3 gene has been reported to be a tumor suppressor and the expression is significantly downregulated in a broad range of cancer cell types. The protein is secretory, but the physiological function remains unclear. This study demonstrated that recombinant REIC/Dkk-3 protein induced the differentiation of human CD14 + monocytes into a novel cell type ( REIC/Dkk-3 Mo). REIC/Dkk-3 Mo resembles immature dendritic cells generated with IL-4 and GM-CSF. Both these cell populations exhibit similar proportions of CD11c + , CD40 + , CD86 + and HLA-DR + cells and endocytic capacity, but REIC/Dkk-3 Mo is negative for CD1a antigen. An analysis of the signal transducers and activators of transcription (STAT) pathways revealed that REIC/Dkk-3 induces phosphorylation of STAT 1 and STAT 3. Furthermore, intratumoral administration of REIC/Dkk-3 protein significantly suppressed tumor growth with CD11c + and CD8 + (dendritic and killer T cell marker, respectively) cell accumulation and enhanced anticancer cytolytic activity of splenocytes. These data indicated a cytokine-like role of REIC/Dkk-3 protein in monocyte differentiation that might be exploited therapeutically.

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“…[1][2][3][4][5][6][7][8] The REIC gene is identical to Dickkopf-3 (Dkk-3) gene and REIC/Dkk-3 has been considered as a tumor suppressor gene to provide a new means of gene therapy for some of the human malignant tumors. The forced expression of REIC/Dkk-3, using a plasmid vector, inhibited cell growth in HeLa and liver cancer cell lines.…”

Section: Introductionmentioning

confidence: 99%

REIC/Dkk-3 overexpression downregulates P-glycoprotein in multidrug-resistant MCF7/ADR cells and induces apoptosis in breast cancer

et al. 2008

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The overexpression of reduced expression in immortalized cells (REIC)/Dickkopf-3 (Dkk-3), a tumor suppressor gene, induced apoptosis in human prostatic and testicular cancer cells. The aim of this study is to examine the potential of REIC/Dkk-3 as a therapeutic target against breast cancer. First, the in vitro apoptotic effect of Ad-REIC treatment was investigated in breast cancer cell lines and the adenovirus-mediated overexpression of REIC/Dkk-3 was thus found to lead to apoptotic cell death in a c-Jun-NH 2 -kinase (JNK) phosphorylaion-dependent manner. Moreover, an in vivo apoptotic effect and MCF/Wt tumor growth inhibition were observed in the mouse model after intratumoral Ad-REIC injection. As multidrug resistance (MDR) is a major problem in the chemotherapy of progressive breast cancer, the in vitro effects of Ad-REIC treatment were investigated in terms of the sensitivity of multidrug-resistant MCF7/ADR cells to doxorubicin and of the P-glycoprotein expression. Ad-REIC treatment in MCF7/ADR cells also downregulated P-glycoprotein expresssion through JNK activation, and sensitized its drug resistance against doxorubicin. Therefore, not only apoptosis induction but also the reversal of anticancer drug resistance was achieved using Ad-REIC. We suggest that REIC/Dkk-3 is a novel target for breast cancer treatment and that Ad-REIC might be an attractive agent against drug-resistant cancer in combination with conventional antineoplastic agents.

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Adenovirus-mediated REIC/Dkk-3 gene transfer inhibits tumor growth and metastasis in an orthotopic prostate cancer model

Cited by 58 publications

References 36 publications

REIC/Dkk-3 stable transfection reduces the malignant phenotype of mouse prostate cancer RM9 cells

REIC/Dkk-3 stable transfection reduces the malignant phenotype of mouse prostate cancer RM9 cells

Immunological aspects of REIC/Dkk-3 in monocyte differentiation and tumor regression

REIC/Dkk-3 overexpression downregulates P-glycoprotein in multidrug-resistant MCF7/ADR cells and induces apoptosis in breast cancer

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