Heat shock proteins play a crucial role in tumor-specific apoptosis by REIC/Dkk-3

Abarzúa, Fernando; Sakaguchi, Masakiyo; Tanimoto, Ryuta; Sonegawa, Hiroyuki; Li, Dai Wei; Edamura, Kohei; Kobayashi, Tomoko; Watanabe, Masami; Kashiwakura, Yuji; Kaku, Haruki; Sakaguchi, Takashi; Nakamura, Keiichiro; Nasu, Yasutomo; Kumon, Hiromi; Huh, Nam

doi:10.3892/ijmm.20.1.37

Cited by 17 publications

(19 citation statements)

References 20 publications

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“…DKK3, a member of the DKK family, has been reported to be associated with the noncanonical Wnt pathway in various cancers (25)(26)(27)(28) and has also been reported to be involved in the canonical pathway in others (12,29). Several studies have indicated that DKK3 functions as a tumor suppressor for human cancer growth and is involved in apoptosis (26)(27)(28)(29).…”

Section: Discussionmentioning

confidence: 99%

Wnt Antagonist Gene DKK2 Is Epigenetically Silenced and Inhibits Renal Cancer Progression through Apoptotic and Cell Cycle Pathways

Hirata

Hinoda

Nakajima

et al. 2009

Clinical Cancer Research

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Purpose: Wnt/β-catenin signaling is involved in renal cancer. DKK2, a Wnt antagonist, is silenced in some cancers, although its function has not been investigated. We hypothesized that DKK2 may be epigenetically silenced and inhibits progression of renal cell carcinoma (RCC). Experimental Design: RCC cell lines and a normal kidney cell line were used for methylation and chromatin immunoprecipitation assays. To assess various functions of DKK2, we established stable DKK2-transfected cells and examined them with regard to cell viability, colony formation, apoptosis, cell cycle, and invasive capability. A total of 52 patients with confirmed conventional RCC were enrolled in this study. Results: RCC cell lines had decreased levels of DKK2, which were significantly increased after treatment with 5-Aza-2′-deoxycytidine alone or 5-Aza-2′-deoxycytidine and trichostatin A. In chromatin immunoprecipitation assay, the levels of acetyl H3, acetyl H4, and dimethylated H3K4 were decreased, whereas the level of dimethylated H3K9 was increased in RCC cell lines compared with HK2 cells. Increased methylation in RCC tissues was associated with higher grades, pathologic stages, and pathologic tumor in RCC. Functional analysis showed that the numbers of viable A498 cells were significantly decreased in DKK2-transfected cells compared with mock cells. The number of apoptotic cells and S/G 2 -M phase cells was significantly increased and decreased after DKK2 transfection, respectively. Corresponding to these results, Bcl2 and cyclin D1 expression were also decreased in DKK2-overexpressing cells. Conclusion: DKK2 is epigenetically silenced by methylation in higher grades and stages of RCC. These results suggest that DKK2 inhibits renal cancer progression through apoptotic and cell cycle pathways. (Clin Cancer Res 2009;15(18):5678-87) Renal cell carcinoma (RCC) is the third leading cause of death among urological tumors, accounting for ∼2% of adult malignancies (1). Although the rate of detection of incidental RCC has increased with improved diagnostic techniques, metastatic lesions are still found at diagnosis in ∼30% of RCC patients (2). Wnt/β-catenin signaling is involved in renal cancer. Canonical Wnt ligands bind to frizzled (FZD) family receptors and the LRP5/LRP6 coreceptor, which stabilize β-catenin. Subsequently, β-catenin interacts with members of the lymphoid enhancer factor 1/T-cell factor family, resulting in generation of a functional transcription factor complex and the expression of downstream target genes (3, 4). Noncanonical Wnt ligands also bind to FZD family receptors and ROR2 and RYK coreceptors (4-7). This signaling is mainly involved in cytoskeletal reorganization during cancer cell invasion and metastasis (6, 7). At present, five Wnt antagonist families have been described, namely, secreted FZD-related protein (sFRP), Wnt inhibitory factor 1, Xenopus Cerberus, Wise, and Dickkopf (DKK) families (8).Among Wnt antagonists, the DKK family consists of four main members (DKK1-DKK4), which contain two disti...

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Section: Discussionmentioning

confidence: 99%

Wnt Antagonist Gene DKK2 Is Epigenetically Silenced and Inhibits Renal Cancer Progression through Apoptotic and Cell Cycle Pathways

Hirata

Hinoda

Nakajima

et al. 2009

Clinical Cancer Research

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“…1,2,5 In prostate cancer PC-3 cells, the overexpression of REIC/Dkk-3 activates JNK, reduces the Bcl-2 protein level, induces the mitochondrial translocation of Bax protein, releases cytochrome c into the cytoplasm, thus finally leading to apoptotic cell death. 1 This study first demonstrated that cleaved caspase-3 was involved in the Ad-REIC-induced apoptotic pathway.…”

Section: Discussionmentioning

confidence: 99%

“…[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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“…REIC/Dkk-3 expression is down-regulated in a broad range of cancer cell lines and clinical cancer materials (2)(3)(4)(5)(6)(7)(8)(9)(10). The expression of the human REIC/Dkk-3 gene is significantly down-regulated in human prostate cancer specimens in comparison to normal human prostate tissue at the protein level (5).…”

Section: Introductionmentioning

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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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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Heat shock proteins play a crucial role in tumor-specific apoptosis by REIC/Dkk-3

Cited by 17 publications

References 20 publications

Wnt Antagonist Gene DKK2 Is Epigenetically Silenced and Inhibits Renal Cancer Progression through Apoptotic and Cell Cycle Pathways

Wnt Antagonist Gene DKK2 Is Epigenetically Silenced and Inhibits Renal Cancer Progression through Apoptotic and Cell Cycle Pathways

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

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

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