WWOX activation by toosendanin suppresses hepatocellular carcinoma metastasis through JAK2/Stat3 and Wnt/β-catenin signaling

Yang, Tianfeng; Xu, Rui; Huo, Jiuyuan; Wang, Bo; Du, Xia; Dai, Bingling; Zhu, Man; Zhan, Yingzhuan; Zhang, Dongdong; Zhang, Yanmin

doi:10.1016/j.canlet.2021.05.010

Cited by 32 publications

(18 citation statements)

References 29 publications

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“…TSN exhibits anticancer effects on numerous types of human cancer cell (32), such as suppresses hepatocellular carcinoma proliferative and metastasis (33), induces the apoptosis of human Ewing's sarcoma (34). In the present study, TSN significantly inhibited proliferation of MKN45 cells in a time-and dose-dependent manner.…”

Section: Discussionsupporting

confidence: 60%

CTPS cytoophidia formation affects cell cycle progression and promotes TSN‑induced apoptosis of MKN45 cells

Chen

Pan

et al. 2022

Mol Med Rep

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Cytidine triphosphate synthase (CTPS) forms filamentous structures termed cytoophidia in numerous types of cell. Toosendanin (TSN) is a tetracyclic triterpenoid and induces CTPS to form cytoophidia in MKN45 cells. However, the effects of CTPS cytoophidia on the proliferation and apoptosis of human gastric cancer cells remain poorly understood. In the present study, CTPS-overexpression and R294D-CTPS mutant vectors were generated to assess the effect of CTPS cytoophidia on the proliferation and apoptosis of gastric cancer MKN45 cells. Formation of CTPS cytoophidia significantly inhibited MKN45 cell proliferation (evaluated using EdU incorporation assay), significantly blocked the cell cycle in G 1 phase (assessed using flow cytometry) and significantly decreased mRNA and protein expression levels of cyclin D1 (assessed by reverse transcription-quantitative PCR and western blotting, respectively). Furthermore, the number of apoptotic bodies and apoptosis rate were markedly elevated and mitochondrial membrane potential was markedly decreased. Moreover, mRNA and protein expression levels of Bax increased and Bcl-2 decreased markedly in MKN45 cells following transfection with the CTPS-overexpression vector. The proliferation rate increased, percentage of G 1 /G 0 -phase cells decreased and apoptosis was attenuated in cells transfected with the R294D-CTPS mutant vector and this mutation did not lead to formation of cytoophidia. The results of the present study suggested that formation of CTPS cytoophidia inhibited proliferation and promoted apoptosis in MKN45 cells. These results may provide insights into the role of CTPS cytoophidia in cancer cell proliferation and apoptosis.

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Section: Discussionsupporting

confidence: 60%

CTPS cytoophidia formation affects cell cycle progression and promotes TSN‑induced apoptosis of MKN45 cells

Chen

Pan

et al. 2022

Mol Med Rep

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“…STAT3, functioned as a transcription factor, is essential for diverse cellular processes. Numerous studies have shown that STAT3 takes part in the occurrence, progression, metastasis, and immune suppression of HCC (27,28). A literature review reported that inhibition of STAT3 pathway can efficiently repre ss the invasion capability of HCC cells vi a downregulating the expressions of MMPs, which play a pivotal role in the digestion of extracellular matrix (29).…”

Section: Discussionmentioning

confidence: 99%

RETRACTED: ACADL Functions as a Tumor Suppressor in Hepatocellular Carcinoma Metastasis by Inhibiting Matrix Metalloproteinase 14

et al. 2022

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High aggressiveness is the main reason for the poor prognosis of hepatocellular carcinoma (HCC) patients. However, its molecular mechanisms still remain largely unexplored. ACADL, a mitochondrial enzyme that facilitates the primary regulated step in mitochondrial fatty acid oxidation, plays a role in HCC growth inhibition. However, the function of ACADL in tumor metastasis is not well elucidated. We found that the reduced expression of ACADL is closely associated with the loss of tumor encapsulation, extrahepatic metastasis, and poor prognosis in HCC patients. Upregulation of ACADL significantly inhibited HCC migration and invasion ability. Whereas knockdown of ACADL markedly enhanced cell invasive capability. Expression of matrix metalloproteinase-14 (MMP14) was negatively associated with the content of ACADL in HCC specimens. MMP14-positive patients with a low expression of ACADL showed worse outcome. Treatment with MMP14 agonist reversed the inhibitory effect of ACADL on HCC metastasis. In addition, ACADL negatively regulated MMP14 expression by inhibiting the STAT3 signaling pathway, as the sustained activation of STAT3 effectively restored the level of MMP14 in ACADL-overexpressed cells. Collectively, these findings disclose that ACADL represses HCC metastasis via STAT3-MMP14 pathway. This study may propose a promising strategy for the precise treatment of metastatic HCC patients.

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“…On this basis, efforts to target the Wnt pathway as a cancer therapy are ongoing. For example, Toosendanin (TSN), a novel WW Domain Containing Oxidoreductase (WWOX) candidate agonist, has significant anti-proliferative and anti-metastatic effects on liver cancers, and functions by accelerating the degradation of β-catenin by promoting the activity of the degradation complex components including APC, AXIN1, CK1 and the GSK3β complex [ 34 ]. In this paper, we identified KCTD9 as a novel tumor suppressor in CRC that similarly acts to increase the degradation of β-catenin.…”

Section: Discussionmentioning

confidence: 99%

“…Activation of Wnt signaling is tightly regulated through the expression and cellular location of the transcription factor β-catenin with increased nuclear expression associated with Wnt signal transduction. It is not surprising that Wnt/β-catenin signaling is also important in tumorigenesis, and indeed when Wnt/β-catenin signaling is inhibited, cell proliferation and metastasis are suppressed in a variety of tumors [34][35][36][37][38]. On this basis, efforts to target the Wnt pathway as a cancer therapy are ongoing.…”

Section: Discussionmentioning

confidence: 99%

KCTD9 inhibits the Wnt/β-catenin pathway by decreasing the level of β-catenin in colorectal cancer

Yao

Ren²,

Wang³

et al. 2022

Cell Death Dis

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Colorectal cancer (CRC) is the second leading cause of cancer mortality worldwide. However, the molecular mechanisms underlying CRC progression remain to be further defined to improve patient outcomes. In this study, we found that KCTD9, a member of the potassium channel tetramerization domain-containing (KCTD) gene family, was commonly downregulated in CRC tissues and that KCTD9 expression was negatively correlated with the clinical CRC stage. Survival analysis showed that patients whose tumors expressed low KCTD9 levels had poorer outcomes. Functional analyses revealed that KCTD9 overexpression inhibited CRC cell proliferation and metastasis, whereas KCTD9 knockdown promoted CRC cell proliferation and metastasis in both in vitro and in vivo models. Manipulating KCTD9 levels in CRC cells via overexpression or knockdown showed KCTD9 expression positively influenced the degradation of β-catenin levels leading to inhibition of Wnt signaling and reductions in Wnt pathway target gene expression. Mechanistically, we found KCTD9 associated with ZNT9 (Zinc Transporter 9), a coactivator of β-catenin-mediated gene transcription. The overexpression of KCTD9 or knockdown of ZNT9 in CRC cells increased the polyubiquitination and proteasomal degradation of β-catenin. In turn, the KCTD9-ZNT9 interaction disrupted interactions between β-catenin and ZNT9, thereby leading to decreased β-catenin target gene expression and the inhibition of Wnt signaling. In conclusion, our findings propose that KCTD9 functions as a tumor suppressor that inhibits CRC cell proliferation and metastasis by inactivating the Wnt/β-catenin pathway. Moreover, its frequent downregulation in CRC suggests KCTD9 as a potential prognostic and therapeutic target in CRC.

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WWOX activation by toosendanin suppresses hepatocellular carcinoma metastasis through JAK2/Stat3 and Wnt/β-catenin signaling

Cited by 32 publications

References 29 publications

CTPS cytoophidia formation affects cell cycle progression and promotes TSN‑induced apoptosis of MKN45 cells

CTPS cytoophidia formation affects cell cycle progression and promotes TSN‑induced apoptosis of MKN45 cells

RETRACTED: ACADL Functions as a Tumor Suppressor in Hepatocellular Carcinoma Metastasis by Inhibiting Matrix Metalloproteinase 14

KCTD9 inhibits the Wnt/β-catenin pathway by decreasing the level of β-catenin in colorectal cancer

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