SMAD4 Suppresses AURKA-Induced Metastatic Phenotypes via Degradation of AURKA in a TGFβ-Independent Manner

Jia, Lei; Lee, Hun Seok; Kundu, Joydeb Kumar; Park, Sang Gyu; Kim, Ryong Nam; Wei, Lihui; Erkín, Özgür Cem; Choi, Jihye; Chae, Seoung Wan; Yang, Hyun-Kwon; Choi, Yoon–La; Shin, Young Kee

doi:10.1158/1541-7786.mcr-14-0191

Cited by 20 publications

(27 citation statements)

References 52 publications

(78 reference statements)

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“…To further confirm, a bimolecular fluorescence complementation (BiFC) assay was performed as previously described. 25 This clearly showed that AIMP1 mainly associated with Smad2 and Smad3 in the cytoplasm (Figure 1b). Competition assay using myc-AIMP1 decreased the interaction between FLAG-VN173-AIMP1 and HA-VC155-Smad2/3 in a dose-dependent manner, further confirming the association of AIMP1 with Smad2 and Smad3 (Figure 1c).…”

Section: Resultsmentioning

confidence: 84%

AIMP1 downregulation restores chondrogenic characteristics of dedifferentiated/degenerated chondrocytes by enhancing TGF-β signal

Ahn

Kumar

et al. 2016

Cell Death Dis

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Dedifferentiation and degeneration of chondrocytes critically influences the efficiency of cartilage repair. One of the causes is the defect of transforming growth factor (TGF)-β signaling that promotes chondrogenic differentiation and degeneration. In the present study, we found that aminoacyl-tRNA synthetase-interacting multifunctional protein 1 (AIMP1) negatively regulates TGF-β signaling via interactions with Smad2 and Smad3 in immunoprecipitation assay and luciferase assay. In addition, we observed that the AIMP1 expression level was significantly increased in osteoarthritis (OA) patient-derived degenerated chondrocytes compared with healthy control. So, we hypothesized that downregulation of AIMP1 using small-interfering RNA (siRNA) technology in dedifferentiated (collected at passage #6) and degenerated (obtained from OA-affected areas) chondrocytes could lead to recover TGF-β signaling in both chondrocytes. Indeed, AIMP1 downregulation restored TGF-β signaling by promoting phosphorylation of Smad2 and Smad3, which shows redifferentiated characteristics in both dedifferentiated and degenerated chondrocytes. Additionally, implantation analyses using in vivo mouse model clearly showed that AIMP1 downregulation resulted in the increased chondrogenic potential as well as the enhanced cartilage tissue formation in both dedifferentiated and degenerated chondrocytes. Histological analyses clarified that AIMP1 downregulation increased expression levels of collagen type II (Col II) and aggrecan, but not Col I expression. Taken together, these data indicate that AIMP1 downregulation using siRNA is a novel tool to restore TGF-β signaling and thereby increases the chondrogenic potential of dedifferentiated/degenerated chondrocytes, which could be further developed as a therapeutic siRNA to treat OA.

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Section: Resultsmentioning

confidence: 84%

AIMP1 downregulation restores chondrogenic characteristics of dedifferentiated/degenerated chondrocytes by enhancing TGF-β signal

Ahn

Kumar

et al. 2016

Cell Death Dis

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“…Results from previous studies have suggested that the overexpression of AURKA increases the level of p-GSK-3β, p-Akt1 and β-catenin and plays an important role in cell proliferation, tumor progression and metastasis [40–42]. MLN8237 is a specific inhibitor of AURKA [43].…”

Section: Discussionmentioning

confidence: 99%

AURKA induces EMT by regulating histone modification through Wnt/β-catenin and PI3K/Akt signaling pathway in gastric cancer

Liu

Song

et al. 2016

Oncotarget

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Gastric cancer, a highly invasive and aggressive malignancy, is the third leading cause of death from cancer worldwide. Genetic association studies have successfully revealed several important genes consistently associated with gastric cancer to date. However, these robust gastric cancer-associated genes do not fully elucidate the mechanisms underlying the development and progression of the disease. In the present study, we performed an alternative approach, a gene expression-based genome-wide association study (eGWAS) across 13 independent microarray experiments (including 251 gastric cancer cases and 428 controls), to identify top candidates (p<0.00001). Additionally, we conducted gene ontology analysis, pathway analysis and network analysis and identified aurora kinase A (AURKA) as our candidate. We observed that MLN8237, which is a specific inhibitor of AURKA, decreased the β-catenin and the phosphorylation of Akt1 and GSK-3β, as well as blocked the Akt and Wnt signaling pathways. Furthermore, MLN8237 arrested the cells in the G2/M phase. The activity of Wnt and Akt signaling pathways affected the level of histone methylation significantly, and we supposed that MLN8237 affected the level of histone methylation through these two signaling pathways. Additionally, the treatment of MLN8237 influenced the level of H3K4 me1/2/3 and H3K27 me1/2/3. Chip data on cell lines suggested that MLN8237 increases the level of H3K27 me3 on the promoter of Twist and inhibits EMT (epithelial-mesenchymal transition). In summary, AURKA is a potential therapeutic target in gastric cancer and induces EMT through histone methylation.

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“…Procedure details were described previously [25] , [26] . The detailed procedure is listed in the supplementary materials and methods.…”

Section: Methodsmentioning

confidence: 99%

Effect of HPV E6/E7 siRNA with Chemotherapeutic Agents on the Regulation of TP53/E2F Dynamic Behavior for Cell Fate Decisions

et al. 2017

Self Cite

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Toxicity and resistance remain major challenges for advanced or recurrent cervical cancer therapies, as treatment requires high doses of chemotherapeutic agents. Restoration of TP53 and hypophosphorylated-retinoblastoma (pRB) proteins by human papillomavirus (HPV) E6/E7 siRNA sensitizes HPV-positive cervical cancer cells toward chemotherapeutic agents. Here, we investigated the therapeutic effects of E6/E7 siRNA on the dynamic behavior of TP53 and RB/E2F signaling networks in deciding the cell fate. The synergistic effect of HPV E6/E7 siRNA pool (SP) with chemotherapeutic agents on TP53 and RB/E2F signaling, proliferation, and apoptosis was analyzed in vitro and in vivo. Compared to the E6/E7 SP alone, E6/E7 SP with cisplatin treatment effectively restored TP53 and RB/E2F signaling and contributes to differences in cell fate, such as apoptosis or cell cycle arrest. We also developed a cellular dynamics model that includes TP53-RB/E2F dynamics and cell proliferation profiles, and confirmed its utility for investigating E6/E7 siRNA-based combination regimens. Using a dual reporter system, we further confirmed the cross talk between TP53 and RB/E2F signaling mechanisms. Treatment of E6/E7 SP cationic liposome (i.v.) with cisplatin and paclitaxel (i.p.) potentially inhibited tumor growth in BALB/c-nude mice. Altogether, our findings suggest that stabilization of TP53 and the RB/E2F repressor complex by E6/E7 SP combined with low-dose chemotherapy can effectively suppress tumor growth.

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SMAD4 Suppresses AURKA-Induced Metastatic Phenotypes via Degradation of AURKA in a TGFβ-Independent Manner

Cited by 20 publications

References 52 publications

AIMP1 downregulation restores chondrogenic characteristics of dedifferentiated/degenerated chondrocytes by enhancing TGF-β signal

AIMP1 downregulation restores chondrogenic characteristics of dedifferentiated/degenerated chondrocytes by enhancing TGF-β signal

AURKA induces EMT by regulating histone modification through Wnt/β-catenin and PI3K/Akt signaling pathway in gastric cancer

Effect of HPV E6/E7 siRNA with Chemotherapeutic Agents on the Regulation of TP53/E2F Dynamic Behavior for Cell Fate Decisions

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