Tumor suppressor REIC/Dkk-3 interacts with the dynein light chain, Tctex-1

Ochiai, Kazuhiko; Watanabe, Masami; Ueki, Hideo; Huang, Peng; Fujii, Yasuyuki; Nasu, Yasutomo; Noguchi, Hirofumi; Hirata, Takeshi; Sakaguchi, Masakiyo; Huh, Nam; Kashiwakura, Yuji; Kaku, Haruki; Kumon, Hiromi

doi:10.1016/j.bbrc.2011.07.109

Cited by 26 publications

(27 citation statements)

References 23 publications

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“…It is also reported that the adenovirusmediated expression of the REIC/Dkk-3 gene efficiently induces endoplasmic reticulum (ER) stress-mediated apoptosis in a manner specific to cancer cells (4,20,21). The present study demonstrated that Ad-REIC treatment induces significant apoptosis in human prostate cancer cells and hepatoma cell lines; however, Ad-REIC treatment does not induce apoptosis in normal human cells.…”

Section: Discussioncontrasting

confidence: 57%

Preclinical biodistribution and safety study of reduced expression in immortalized cells/Dickkopf-3-encoding adenoviral vector for prostate cancer gene therapy

et al. 2012

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The biodistribution and safety of adenoviral vectors encoding the human REIC/Dkk-3 tumor suppressor gene (Ad-REIC) were examined in this preclinical study for in situ prostate cancer gene therapy. First, the in vitro apoptotic effects of Ad-REIC in normal and cancer cells derived from the prostate and liver were examined. Significant apoptotic effects were observed at 100 MOI (multiplicity of infection) in prostate cancer cells (LNCaP, PC3) and hepatoma cells (HEP3B and HEPG2); however, no effects were seen in normal cells. To analyze the safety of intraprostatic Ad-REIC administration, the biodistribution and histology after Ad-REIC injection were evaluated in various organs of normal male C57BL6 mice. In a supporting study, vector dissemination following intravenous injection of Ad-REIC into tail veins was determined. To evaluate whether Ad-REIC was present in the collected tissue specimens, human REIC gene detection was performed using DNA-PCR. Intraprostatic treatment administered at lower doses showed vector biodistribution into the colon, urinary bladder and prostate. At higher doses, vector dissemination was observed in tissues more distant from the prostate, including the lung, thymus, heart, liver and adrenal gland. After intravenous injection of Ad-REIC, dissemination was observed in the liver and spleen. These results indicate that the biodistribution of Ad-REIC is determined by the dose and route of administration. Although acute inflammatory effects were observed in the prostate after intraprostatic administration at higher doses, no abnormal histological findings were noted in the other tissues, including those of intravenously treated mice. Regarding the safety of Ad-REIC administration, no deaths and no signs of toxicity or unusual behavior were observed in the mice in any treatment group. Based on these preclinical experiments, adenovirus-mediated in situ REIC/Dkk-3 gene therapy is considered to be safe for use as a treatment for human prostate cancer.

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Section: Discussioncontrasting

confidence: 57%

Preclinical biodistribution and safety study of reduced expression in immortalized cells/Dickkopf-3-encoding adenoviral vector for prostate cancer gene therapy

et al. 2012

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“…The binding partner of intracellular REIC/Dkk-3 protein has been investigated by several previous studies. It has been reported that Dkk-3 binds to other proteins, such as Kremen1/2 (28,29), β-TrCP (30) and TcTex-1 (31), and that these interactions occur in the cytoplasm. These proteins include substantial molecules that significantly affect and modify intracellular signaling pathways, including the Wnt and TGF-β (16,32).…”

Section: Physiological Functions Of Reic/dkk-3mentioning

confidence: 99%

Adenovirus-mediated REIC/Dkk-3 gene therapy: Development of an autologous cancer vaccination therapy (Review)

2013

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Reduced expression in immortalized cells (REIC)/Dickkopf (Dkk)-3 is a tumor suppressor and therapeutic gene and has been studied with respect to the application of cancer gene therapy. Our previous studies demonstrated that the intratumoral injection of an adenovirus vector carrying the human REIC/Dkk-3 gene (Ad-REIC) suppresses tumor growth in mouse models of prostate, breast and testicular cancer and malignant mesothelioma. The mechanisms underlying these antitumor therapeutic effects have only been clarified recently. It has been demonstrated that Ad-REIC treatment inhibits cancer progression via the upregulation of systemic anticancer immunity. Under experimental conditions, autologous cancer vaccination via cancer-specific apoptosis and anticancer immune activation is a possible therapeutic mechanism. The robust anticancer effects observed in previous preclinical studies support the clinical utility of Ad-REIC. At present, a phase I–IIa study of Ad-REIC gene therapy in prostate cancer patients is ongoing. The current study reviews the observations of previous fundamental studies and summarizes the anticancer mechanisms of intratumoral Ad-REIC treatment in terms of cancer vaccination.

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“…Dkk-1, -2 and -4 inhibit Wnt/b-catenin signals by binding to LRP5/6 (Niehrs, 2006), but Dkk-3 does not bind to these proteins directly (Mao and Niehrs, 2003;Mao et al, 2001). Instead, Dkk-3 has been reported to affect Wnt signalling through binding other proteins, namely Kremen1/2 (Nakamura and Hackam, 2010), b-TrcP (Lee et al, 2009) and TcTex-1 (Ochiai et al, 2011). However, Dkk-3 is a secreted protein and the relevance of these interactions, which take place in the cytoplasm, to the function of endogenous Dkk-3 remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Downregulation of Dickkopf-3 disrupts prostate acinar morphogenesis through TGF-β/Smad signaling

Romero

Kawano

Bengoa³

et al. 2013

Journal of Cell Science

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SummaryLoss of tissue organization is a hallmark of the early stages of cancer, and there is considerable interest in proteins that maintain normal tissue architecture. Prostate epithelial cells cultured in Matrigel form three-dimensional acini that mimic aspects of prostate gland development. The organization of these structures requires the tumor suppressor Dickkopf-3 (Dkk-3), a divergent member of the Dkk family of secreted Wnt signalling antagonists that is frequently downregulated in prostate cancer. To gain further insight into the function of Dkk-3 in the prostate, we compared the prostates of Dkk3-null mice with those of control littermates. We found increased proliferation of prostate epithelial cells in the mutant mice and changes in prostate tissue organization. Consistent with these observations, cell proliferation was elevated in acini formed by human prostate epithelial cells stably silenced for Dkk-3. Silencing of Dkk-3 increased TGF-b/Smad signalling, and inhibitors of TGF-b/Smad signalling rescued the defective acinar phenotype caused by loss of Dkk-3. These findings suggest that Dkk-3 maintains the structural integrity of the prostate gland by limiting TGF-b/Smad signalling.

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Tumor suppressor REIC/Dkk-3 interacts with the dynein light chain, Tctex-1

Abstract: Running title: REIC/Dkk-3 interacts with Tctex-1. The link between REIC/Dkk-3 and Tctex-1 may be of significance for understanding the molecular functions of the proteins in ER stress signaling and intracellular dynein motor dynamics, respectively.

Cited by 26 publications

References 23 publications

Preclinical biodistribution and safety study of reduced expression in immortalized cells/Dickkopf-3-encoding adenoviral vector for prostate cancer gene therapy

Preclinical biodistribution and safety study of reduced expression in immortalized cells/Dickkopf-3-encoding adenoviral vector for prostate cancer gene therapy

Adenovirus-mediated REIC/Dkk-3 gene therapy: Development of an autologous cancer vaccination therapy (Review)

Downregulation of Dickkopf-3 disrupts prostate acinar morphogenesis through TGF-β/Smad signaling

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