The tumor suppressor DAP-kinase links cell adhesion and cytoskeleton reorganization to cell death regulation

Chen, Ruey‐Hwa; Wang, Won Jing; Kuo, Jean Cheng

doi:10.1007/s11373-005-9063-5

Cited by 20 publications

(14 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It has been well established that the reorganization of the actin cytoskeleton has effects on cellular proliferation, adhesion and migration (23,24). ROCK1 may be activated by binding to the active guanosine triphosphate-bound form of Rho, further interacting with the actin cytoskeleton, and therefore has a key role in cytoskeletal reorganization (25).…”

Section: Discussionmentioning

confidence: 99%

microRNA-145 inhibits osteosarcoma cell proliferation and invasion by targeting ROCK1

Lei

Xie

Wang

et al. 2014

Molecular Medicine Reports

View full text Add to dashboard Cite

Abstract. Osteosarcoma (OS), a malignant mesenchymal sarcoma, is the most frequent primary bone tumor, with a peak incidence in young children and adolescents. The downregulation of microRNA-145 (miRNA/miR-145) has previously been identified to be associated with the aggressiveness and metastasis of OS. However, the detailed regulatory mechanism by which miR-145 inhibits OS remains largely unknown. The present study demonstrated that miR-145 was significantly downregulated in OS tissues and KHOS and U2OS cell lines. Rho-associated protein kinase 1 (ROCK1), a key regulator of actin cytoskeleton reorganization, was identified as a novel target of miR-145. Ectopic expression of miR-145 notably suppressed the protein expression of ROCK1 without affecting its mRNA level. Furthermore, the expression of ROCK1 was significantly increased in the OS tissues and in the KHOS and U2OS cells. It was further demonstrated that the overexpression of miR-145 downregulated KHOS and U2OS cell proliferation and invasion, which was reversed by restoration of ROCK1. To the best of our knowledge, the present study demonstrates for the first time that, as a tumor suppressor, miRNA-145 inhibits OS cell proliferation and invasion, at least in part by directly targeting ROCK1. These results indicate that miR-145 may be a potential candidate for the diagnosis and treatment of OS. IntroductionOsteosarcoma (OS) mainly arises from the metaphysis of the long bones of adolescents and young adults. OS is the most common primary malignant tumor and is associated with high morbidity (1). Despite wide tumor excision combining multi-agent chemotherapy and radiotherapy, the five-year survival rate of patients with recurrent or metastatic OS remains at ~30% (2). Although recent studies have focused on the molecular pathogenesis of OS (3), its detailed molecular mechanisms have not been fully elucidated. As a result, the identification of novel molecular candidates and/or targets is crucial for the development of effective therapeutic strategies to improve the prognosis of OS.microRNAs (miRNA/miRs) are small non-coding RNA molecules with 18-25 nucleotides, which mainly negatively regulate gene expression by suppressing translation via binding to the 3' untranslated region (3'UTR) of their target genes (4). Previously, miRNAs have been demonstrated to have crucial roles in various physiological and pathological processes, including the development and progression of malignant tumors (5). In fact, it has been demonstrated that miRNAs function as oncogenes or tumor suppressors in cellular proliferation, apoptosis, differentiation, migration and invasion in various cancer cells (6,7). Despite indications that several miRNAs, including miR-20a, miR-199a-3p, miR-143 and so forth, are involved in the development and progression of OS (8-10), their exact role remains largely unknown. Previously, miR-145 was identified as a tumor-suppressive miRNA in multiple types of cancers, including lung, glioma, ovarian, colon, gastric, bladder, prostate and breast cancer, ...

show abstract

Section: Discussionmentioning

confidence: 99%

microRNA-145 inhibits osteosarcoma cell proliferation and invasion by targeting ROCK1

Lei

Xie

Wang

et al. 2014

Molecular Medicine Reports

View full text Add to dashboard Cite

show abstract

“…The upregulation of DAPK was observed to increase cell turnover and arterial wall instability, which increased susceptibility to low-density lipoprotein absorption (12). DAPK may function as a tumor suppressor due to its ability to promote apoptosis and autophagy (13,14), suppress cellular transformation (15) and inhibit metastasis (16,17). Additionally, DAPK may be activated by various stimuli, including tumor necrosis factor (TNF-α), interferon-γ and p53; therefore, acts as a converging point for apoptotic signaling (17–19).…”

Section: Introductionmentioning

confidence: 99%

Upregulation of DAPK contributes to homocysteine-induced endothelial apoptosis via the modulation of Bcl2/Bax and activation of caspase 3

Tian

Shi

Liu

et al. 2016

Molecular Medicine Reports

View full text Add to dashboard Cite

Hyperhomocysteinemia is characterized by an abnormally high level of homocysteine (Hcy) in the blood and is associated with cardiovascular diseases such as atherosclerosis. Endothelial dysfunction may lead to the pro-atherogenic effects associated with hyperhomocysteinemia. Endothelial dysfunction induced by Hcy has been previously investigated; however, the underlying molecular mechanism remains to be fully elucidated. The present study investigated whether death-associated protein kinase (DAPK) is involved in Hcy-induced apoptosis in human umbilical vein endothelial cells (HUVECs). It was determined that Hcy treatment upregulated the mRNA and protein expression levels of DAPK in HUVECs. Additionally, it was identified that the knockdown of DAPK using small interfering RNA may attenuate the Hcy-induced apoptosis and dissipation of mitochondrial membrane potential. DAPK inhibition may also reverse the effect of Hcy by the upregulation of B cell leukemia/lymphoma 2 (Bcl2) and poly ADP-ribose polymerase, and the downregulation of Bcl2-associated X protein (Bax) and of caspase 3. In conclusion, the present study demonstrated that DAPK contributed to the Hcy-induced endothelial apoptosis via modulation of Bcl2/Bax expression levels and activation of caspase 3.

show abstract

“…31 Thirteen pathways involving anoikis were identified (data not shown). Among them, the mRNA level of DAPK (a kinase involved in pro-anoikis and metastasis suppression 32, 33 ) was upregulated 5.36-fold in CL1-5/CCN2 compared with control (Supplementary Table S1). In CL1-5 cells, we found increased levels of promoter activity and transcription of DAPK associated with the ectopic expression of CCN2 or its CT domain.…”

Section: Resultsmentioning

confidence: 99%

CCN2 inhibits lung cancer metastasis through promoting DAPK-dependent anoikis and inducing EGFR degradation

et al. 2012

View full text Add to dashboard Cite

CCN family protein 2 (CCN2), also known as connective tissue growth factor, is a secreting protein that modulates multiple cellular events. We previously demonstrated the metastasis-suppressive effect of CCN2 in lung cancer cells. In this study, we investigate the role of CCN2 in anoikis, a form of programmed cell death that is critical in suppressing cancer metastasis. CCN2 binds to the epidermal growth factor receptor (EGFR) and triggers ubiquitination by inhibiting the formation of the β-pix/Cbl complex, resulting in the degradation of EGFR. Binding of CCN2 to EGFR suppresses the phosphorylation of c-Src and extracellular signal-regulated kinase but increases the expression of death-associated protein kinase, which leads to anoikis. Overall, our findings provide evidence validating the use of CCN2 as an anti-metastatic therapy in lung cancer patients, and prospect a potential therapeutic synergy between CCN2 and the anti-EGFR antibody for the treatment of lung cancer.

show abstract

The tumor suppressor DAP-kinase links cell adhesion and cytoskeleton reorganization to cell death regulation

Cited by 20 publications

References 53 publications

microRNA-145 inhibits osteosarcoma cell proliferation and invasion by targeting ROCK1

microRNA-145 inhibits osteosarcoma cell proliferation and invasion by targeting ROCK1

Upregulation of DAPK contributes to homocysteine-induced endothelial apoptosis via the modulation of Bcl2/Bax and activation of caspase 3

CCN2 inhibits lung cancer metastasis through promoting DAPK-dependent anoikis and inducing EGFR degradation

Contact Info

Product

Resources

About