Down-regulation of Inhibition of Differentiation-1 via Activation of Activating Transcription Factor 3 and Smad Regulates REIC/Dickkopf-3–Induced Apoptosis

Kashiwakura, Yuji; Ochiai, Kazuhiko; Watanabe, Masami; Abarzúa, Fernando; Sakaguchi, Masakiyo; Takaoka, Munenori; Tanimoto, Ryuta; Nasu, Yasutomo; Huh, Nam; Kumon, Hiromi

doi:10.1158/0008-5472.can-08-0080

Cited by 86 publications

(124 citation statements)

References 25 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: 93%

“…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%

“…Adenovirus vector mediated overexpression of REIC/ Dkk-3 selectively induces apoptosis in prostatic cancer cells through the activation of c-Jun-NH 2 -kinase (JNK) and c-Jun but not in non-cancer cells (5). Adenovirus mediated REIC/ Dkk-3 overexpression inhibits the expression of Id-1, which works in cell cycle progression, anti-apoptosis and angiogenesis (12) in malignant mesothelioma cells (9). These findings strongly suggest that REIC/Dkk-3 plays a role in the inhibition of tumor progression in a broad range of human malignancies.…”

Section: Introductionmentioning

confidence: 99%

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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: 93%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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“…However, this does not sufficiently exclude other mechanisms, since a number of apoptotic signaling pathways are involved in the progression of lung cancer (37,38). In another respect, Dkk3 regulates cell proliferation and apoptosis in a complex manner, as Dkk3 may also directly or indirectly modulate apoptosis via the mitochondrial pathway and c-Jun N-terminal kinase (JNK) signaling pathway (44)(45)(46). The genome-wide assay has also shown that Wnt inhibition by β-catenin knockout alters over 130 gene expressions and regulates the PI3K/Akt, NF-κB and p53 pathways which play a crucial role in cell apoptosis (47).…”

Section: Discussionmentioning

confidence: 99%

Dickkopf-3 (Dkk3) induces apoptosis in cisplatin-resistant lung adenocarcinoma cells via the Wnt/β-catenin pathway

Wang

et al. 2014

Oncology Reports

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Abstract. Previous studies have shown that is inactivated in lung cancer cells, while the inactivation of the Wnt/β-catenin signaling pathway by Dkk3 inhibits lung cancer progression. In the present study, we investigated whether Dkk3 enhances the sensitivity of lung cancer cells to cisplatin. A549, Calu1 and H460 lung adenocarcinoma cell lines were transfected with DKK3 siRNA, while the cisplatin-resistant subline A549cis was transfected with DKK3. DKK3 expression was attenuated in A549cis, Calu1cis and H460cis compared to A549, Calu1 and H460, respectively. Lung adenocarcinoma cell growth, proliferation, apoptosis, cell cycle in vitro and in vivo were then analyzed. DKK3 knockdown by siRNA transfection rendered A549, Calu1 and H460 resistant to cisplatin. As a result of DKK3 transfection, the expression of DKK3 and E-cadherin was significantly upregulated, while that of MMP7, survivin, c-myc and cyclin D1 was downregulated. DKK3 overexpression retarded cell proliferation, induced cell cycle arrest and apoptosis, and reduced cell invasive ability in the A549 and A549cis cells. In addition, the proportions of apoptotic cells and the PARP level were significantly increased in A549cis-and H460cis-DKK3 cells treated with cisplatin. Moreover, tumor growth was retarded more in cisplatin-treated nude mice seeded with A549cis-DKK3 cells than with A549cis cells. Cell viability increased with the pretreatment of SB216763 for 2 h in A549cis and A549cis-DKK3 cells incubated with cisplatin (1 µM) for 72 h. In conclusion, the re-activation of Dkk3 enhances the chemosensitivity to cisplatin in cisplatin-resistant lung adenocarcinoma cell lines, which requires additional studies to realize this potential in clinical use. IntroductionLung cancer has emerged as the third leading cause of cancer-related mortality worldwide (1). In the USA, over 200,000 new lung cancer cases are diagnosed annually, causing over 150,000 deaths in one year (1). Approximately 85% of lung cancer patients suffer from non-small cell lung cancer (NSCLC). Due to the comparative therapeutic advantage, cisplatin-based combination regimens are recommended as the optimal choice currently for the majority of NSCLC patients indicative of chemotherapy or adjuvant chemotherapy (2). However, the average survival time for patients with advanced stage of NSCLC receiving cisplatin plus gemcitabine treatment is ~16 months and may even be reduced to 12 months in those with cisplatin-resistance (3). The dilemma in managing late-stage NSCLC requires the elucidation of the mechanisms in cisplatin resistance to define novel, effective and applicable therapeutic targets for lung cancer (2,3).Several signal transduction pathways controlling chemosensitivity are aberrantly activated in various types of cancer, among which Wnt is of special significance (4). The role of Wnt1/Int-1 in the induction of mouse mammary tumor as an integration site for mouse mammary tumor virus (MMTV) was first recognized 30 years ago (4). Wnt/β-catenin signaling is initiated by the binding of secre...

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“…The expression of REIC/Dkk-3 was reduced in many human cancer cells and tissues, including prostate cancer (2), renal clear cell carcinoma (3), testicular (4), non-small cell lung (5) and cervical cancer (6), malignant glioma (7), and malignant mesothelioma (8). Overexpression of REIC/Dkk-3 gene using an adenovirus vector (Ad-REIC) induced apoptosis in various human cancers.…”

Section: Introductionmentioning

confidence: 99%

Internalization of REIC/Dkk-3 protein by induced pluripotent stem cell-derived embryoid bodies and extra-embryonic tissues

Kataoka

Sakaguchi²,

et al. 2010

Int J Mol Med

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Abstract. REIC/Dkk-3 was first identified as a downregulated gene in a number of human immortalized cells and human tumor-derived cell lines. Overexpression of the REIC/Dkk-3 gene using an adenovirus vector (Ad-REIC) has showed a potent selective therapeutic effect on various human cancers through induction of ER stress. Furthermore, we recently showed that Ad-REIC has an indirect host-mediated anti-tumor activity by induction of IL-7. However, the physiological function of REIC/Dkk-3 is still unclear. As a first step to study the possible receptor(s) for secreted REIC/Dkk-3, we analyzed the internalization of Cy3-labeled recombinant REIC/Dkk-3 protein. Among the cell lines screened, mouse induced pluripotent stem (iPS) cells showed a unique pattern of internalization. The internalization was observed in peripheral cells of spherical colonies formed spontaneously, but not in undifferentiated iPS cells. When we analyzed embryoid bodies (EBs) derived from iPS cells, REIC/Dkk-3 protein was internalized specifically by differentiated cells located at the periphery of EBs. Interestingly, Dkk-1 was internalized by undifferentiated cells at the center of the EBs. When developmental tissue was analyzed, internalization of REIC/Dkk-3 protein was strictly limited to extra-embryonic tissue, such as the trophectoderm layer of 4.5 days post-coitus (dpc) blastocysts and the chorionic membrane at 16.5 dpc. The mechanism of the internalization was confirmed to be endocytosis. These findings will contribute to knowledge on the interaction of REIC/Dkk-3 with a possible receptor(s).

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Down-regulation of Inhibition of Differentiation-1 via Activation of Activating Transcription Factor 3 and Smad Regulates REIC/Dickkopf-3–Induced Apoptosis

Cited by 86 publications

References 25 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

Dickkopf-3 (Dkk3) induces apoptosis in cisplatin-resistant lung adenocarcinoma cells via the Wnt/β-catenin pathway

Internalization of REIC/Dkk-3 protein by induced pluripotent stem cell-derived embryoid bodies and extra-embryonic tissues

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