Chemically synthesized cinobufagin suppresses nasopharyngeal carcinoma metastasis by inducing ENKUR to stabilize p53 expression

Hou, Rentao; Xiong, Liu; Yang, Huiling; Deng, Shuting; Chen, Cheng; Li, Yonghao; Zhang, Yewei; Jiang, Jingwen; Zhu, Zhibo; Su, Yun; Wu, Liyang; Xie, Yingying; Li, Xiaoning; Li, Wenmin; Liu, Zhen; Fang, Weiyi

doi:10.1016/j.canlet.2022.01.025

Cited by 23 publications

(24 citation statements)

References 46 publications

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“…Studies have shown that the PI3K pathway is involved in the migration, invasion and EMT of HCC cells ( 39 , 46 ). The effects of different concentrations of DHW-208 on the migration and invasion of Hep3B and Bel7402 cells were investigated.…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, mTOR can act on the transcription factor slug and inhibit its expression by binding to the promoter of E-cadherin (36)(37)(38). Slug also promotes the expression of MMP-9 and MMP-2 to activate EMT (39). In angiogenesis, mTOR mediates its effects by phosphorylating 4E-BP1 and disrupting the integrity of the complex formed by mTOR and 4E-BP1, which is critical for inhibiting the translation of related genes and enhances HIF-1a translation (40,41).…”

mentioning

confidence: 99%

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DHW-208, A Novel Phosphatidylinositol 3-Kinase (PI3K) Inhibitor, Has Anti-Hepatocellular Carcinoma Activity Through Promoting Apoptosis and Inhibiting Angiogenesis

Wang

Liu

et al. 2022

Front. Oncol.

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Hepatocellular carcinoma (HCC) is one of the most common tumors worldwide with high prevalence and lethality. Due to insidious onset and lack of early symptoms, most HCC patients are diagnosed at advanced stages without adequate methods but systemic therapies. PI3K/AKT/mTOR signaling pathway plays a crucial role in the progression and development of HCC. Aberrant activation of PI3K/AKT/mTOR pathway is involved in diverse biological processes, including cell proliferation, apoptosis, migration, invasion and angiogenesis. Therefore, the development of PI3K-targeted inhibitors is of great significance for the treatment of HCC. DHW-208 is a novel 4-aminoquinazoline derivative pan-PI3K inhibitor. This study aimed to assess the therapeutic efficacy of DHW-208 in HCC and investigate its underlying mechanism. DHW-208 could inhibit the proliferation, migration, invasion and angiogenesis of HCC through the PI3K/AKT/mTOR signaling pathway in vitro. Consistent with the in vitro results, in vivo studies demonstrated that DHW-208 elicits an antitumor effect by inhibiting the PI3K/AKT/mTOR-signaling pathway with a high degree of safety in HCC. Therefore, DHW-208 is a candidate compound to be developed as a small molecule PI3K inhibitor for the treatment of HCC, and our study provides a certain theoretical basis for the treatment of HCC and the development of PI3K inhibitors.

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

DHW-208, A Novel Phosphatidylinositol 3-Kinase (PI3K) Inhibitor, Has Anti-Hepatocellular Carcinoma Activity Through Promoting Apoptosis and Inhibiting Angiogenesis

Wang

Liu

et al. 2022

Front. Oncol.

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“…Although MYH9 was originally identified as a tumor suppressive factor in squamous cell carcinoma of head and neck, 17 recent studies support a role for MYH9 as an oncoprotein in many tumors, including GC 18–23 . Interestingly, in previous studies, we have demonstrated that MYH9 interacted with ENKUR and antagonized ENKUR to induce‐cell growth and metastasis in hepatocellular carcinoma, lung adenocarcinoma, and nasopharyngeal carcinoma via suppressing p53 or elevating c‐Myc 13–15 . Nevertheless, there is no document to clarify the mechanism of ENKUR to modulate MYH9 in GC.…”

Section: Introductionmentioning

confidence: 90%

“… 18 , 19 , 20 , 21 , 22 , 23 Interestingly, in previous studies, we have demonstrated that MYH9 interacted with ENKUR and antagonized ENKUR to induce‐cell growth and metastasis in hepatocellular carcinoma, lung adenocarcinoma, and nasopharyngeal carcinoma via suppressing p53 or elevating c‐Myc. 13 , 14 , 15 Nevertheless, there is no document to clarify the mechanism of ENKUR to modulate MYH9 in GC.…”

Section: Introductionmentioning

confidence: 99%

“…Subsequently, ENKUR has shown promising antitumor ability to decrease cell migration and invasion in lung adenocarcinoma and colorectal cancer 11,12 . Our recent studies also showed that the ENKUR was an important tumor suppressor and mediated the small molecule chemical compound cinobufotalin to inhibit tumor proliferation, metastasis, and chemoresistance in nasopharyngeal carcinoma, hepatocellular carcinoma, and lung adenocarcinoma 13–15 . However, the influence of the ENKUR on the biological function of GC and its related molecular mechanisms have not yet been studied.…”

Section: Introductionmentioning

confidence: 99%

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ENKUR recruits FBXW7 to ubiquitinate and degrade MYH9 and further suppress MYH9‐induced deubiquitination of β‐catenin to block gastric cancer metastasis

Zhan

Yan

Yang

et al. 2022

MedComm

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ENKUR was shown as a suppressor in some tumors. However, the biological role of ENKUR on gastric cancer (GC) and its related molecular mechanisms is not clear. Here, we first observed that ENKUR significantly inhibited cell migration, invasion, and metastasis in GC. The molecular basis showed β‐catenin‐mediated epithelial‐mesenchymal transition (EMT) signaling was inactivated in ENKUR‐overexpressing GC cells. In addition, ENKUR knockdown markedly restored cell migration and invasion. Subsequently, ENKUR bound to MYH9 and decreased its protein expression by recruiting E3 ubiquitin ligase FBXW7 to form an ubiquitinated degradation complex. The downregulated MYH9 protein weakened the recruitment of the deubiquitinase USP2 and thus promoted the degradation of β‐catenin protein, which finally suppressed EMT signaling. Finally, the oncogenic transcription factor c‐Jun bound to ENKUR promoter and reduced its expression in GC. In clinical samples, decreased ENKUR expression promoted the unfavorable prognosis of GC. Our data proved the vital role of ENKUR on suppressing cell migration, invasion, and metastasis and demonstrated its potential as a therapeutic target for GC.

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MYH10 Combines with MYH9 to Recruit USP45 by Deubiquitinating Snail and Promotes Serous Ovarian Cancer Carcinogenesis, Progression, and Cisplatin Resistance

et al. 2023

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The poor prognosis of serous ovarian cancer (SOC) is due to its high invasive capacity and cisplatin resistance of SOC cells, whereas the molecular mechanisms remain poorly understood. In the present study, the expression and function of non‐muscle myosin heavy chain IIB (MYH10) in SOC are identified by immunohistochemistry, in vitro, and in vivo studies, respectively. The mechanism of MYH10 is demonstrated by co‐immunoprecipitation, GST pull‐down, confocal laser assays, and so on. The results show that the knockdown of MYH10 suppressed SOC cell proliferation, migration, invasion, metastasis, and cisplatin resistance both in vivo and in vitro. Further studies confirm that the MYH10 protein functional domain combines with non‐muscle myosin heavy chain IIA (MYH9) to recruit the deubiquitinating enzyme Ubiquitin‐specific proteases 45 and deubiquitinates snail to inhibit snail degradation, eventually promoting tumorigenesis, progression, and cisplatin resistance in SOC. In clinical samples, MYH10 expression is significantly elevated in SOC samples compared to the paratumor samples. And the expression of MYH10 is positively correlated with MYH9 expression. MYH10+/MYH9+ co‐expression is an independent prognostic factor for predicting SOC patient survival. These findings uncover a key role of the MYH10‐MYH9‐snail axis in SOC carcinogenesis, progression, and cisplatin resistance, and provide potential novel therapeutic targets for SOC intervention.

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Chemically synthesized cinobufagin suppresses nasopharyngeal carcinoma metastasis by inducing ENKUR to stabilize p53 expression

Cited by 23 publications

References 46 publications

DHW-208, A Novel Phosphatidylinositol 3-Kinase (PI3K) Inhibitor, Has Anti-Hepatocellular Carcinoma Activity Through Promoting Apoptosis and Inhibiting Angiogenesis

DHW-208, A Novel Phosphatidylinositol 3-Kinase (PI3K) Inhibitor, Has Anti-Hepatocellular Carcinoma Activity Through Promoting Apoptosis and Inhibiting Angiogenesis

ENKUR recruits FBXW7 to ubiquitinate and degrade MYH9 and further suppress MYH9‐induced deubiquitination of β‐catenin to block gastric cancer metastasis

MYH10 Combines with MYH9 to Recruit USP45 by Deubiquitinating Snail and Promotes Serous Ovarian Cancer Carcinogenesis, Progression, and Cisplatin Resistance

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