Dihydroartemisinin enhances VEGFR1 expression through up-regulation of ETS-1 transcription factor

Niu, Na; Yu, Chang-Mei; Li, Liqun; Liu, Qiang; Zhang, Wenqian; Liang, Kai‐Li; Zhu, Guoping; Li, Jing; Zhou, Xia; Tang, Jin‐Bao; Liu, Ju

doi:10.7150/jca.25082

Cited by 11 publications

(7 citation statements)

References 50 publications

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“…Youyou Tu awarded the Nobel Prize in physiology or medicine in 2015 for her great contribution to discover the antimalarial effect of artemisinin. Dihydroartemisinin (DHA), one of the derivatives of artemisinin, was found to own anticancer effects on numerous kinds of cancers [9,10,32]. The study of the anticancer effect of DHA on esophageal cancer is limited.…”

Section: Discussionmentioning

confidence: 99%

Autophagy-dependent cell cycle arrest in esophageal cancer cells exposed to dihydroartemisinin

Liao

Liu

et al. 2020

Chin Med

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Background: Dihydroartemisinin (DHA), a derivate of artemisinin, is an effective antimalarial agent. DHA has been shown to exert anticancer activities to numerous cancer cells in the past few years, while the exact molecular mechanisms remain to be elucidated, especially in esophageal cancer. Methods: Crystal violet assay was conducted to determine the cell viability of human esophageal cancer cell line Eca109 treated with DHA. Tumor-bearing nude mice were employed to evaluate the anticancer effect of DHA in vivo. Soft agar and crystal violet assays were used to measure the tumorigenicity of Eca109 cells. Flow cytometry was performed to evaluate ROS or cell cycle distribution. GFP-LC3 plasmids were delivered into Eca109 cells to visualize autophagy induced by DHA under a fluorescence microscope. The mRNA and protein levels of each gene were tested by qRT-PCR and western blot, respectively. Results: Our results proved that DHA significantly reduced the viability of Eca109 cells in a dose-and time-dependent manner. Further investigation showed that DHA evidently induced cell cycle arrest at the G2/M phase in Eca109 cells. Mechanistically, DHA induced intracellular ROS generation and autophagy in Eca109 cells, while blocking ROS by an antioxidant NAC obviously inhibited autophagy. Furthermore, we found that telomere shelterin component TRF2 was down-regulated in Eca109 cells exposed to DHA through autophagy-dependent degradation, which could be rescued after autophagy was blocked by ROS inhibition. Moreover, the DNA damage response (DDR) was induced obviously in DHA treated cells. To further explore whether ROS or autophagy played a vital role in DHA induced cell cycle arrest, the cell cycle distribution of Eca109 cells was evaluated after ROS or autophagy blocking, and the results showed that autophagy, but not ROS, was essential for cell cycle arrest in DHA treated cells. Conclusion: Taken together, DHA showed anticancer effect on esophageal cancer cells through autophagy-dependent cell cycle arrest at the G2/M phase, which unveiled a novel mechanism of DHA as a chemotherapeutic agent, and the degradation of TRF2 followed by DDR might be responsible for this cell phenotype.

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Section: Discussionmentioning

confidence: 99%

Autophagy-dependent cell cycle arrest in esophageal cancer cells exposed to dihydroartemisinin

Liao

Liu

et al. 2020

Chin Med

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“…It has been shown that DHA induces autophagy in human umbilical vein endothelial cells by inhibiting Akt and mTOR signaling pathways, thereby inhibiting their ability to generate blood vessels in vitro (66). In addition, DHA also inhibits angiogenesis by increasing the expression of VEFGR1, a deceptive receptor of VEGF, to block the binding of VEGF and VEFGR2 (67). Li et al find that DHA inhibits esophageal cancer growth and metastasis by inhibiting the phosphorylation of p65 and reducing the activity of HIF-1a and VEGF (40).…”

Section: Inhibition Of Tumor Metastasismentioning

confidence: 99%

Dihydroartemisinin: A Potential Drug for the Treatment of Malignancies and Inflammatory Diseases

Jin

Fujimoto

2021

Front. Oncol.

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Dihydroartemisinin (DHA) has been globally recognized for its efficacy and safety in the clinical treatment of malaria for decades. Recently, it has been found that DHA inhibits malignant tumor growth and regulates immune system function in addition to anti-malaria. In parasites and tumors, DHA causes severe oxidative stress by inducing excessive reactive oxygen species production. DHA also kills tumor cells by inducing programmed cell death, blocking cell cycle and enhancing anti-tumor immunity. In addition, DHA inhibits inflammation by reducing the inflammatory cells infiltration and suppressing the production of pro-inflammatory cytokines. Further, genomics, proteomics, metabolomics and network pharmacology of DHA therapy provide the basis for elucidating the pharmacological effects of DHA. This review provides a summary of the recent research progress of DHA in anti-tumor, inhibition of inflammatory diseases and the relevant pharmacological mechanisms. With further research of DHA, it is likely that DHA will become an alternative therapy in the clinical treatment of malignant tumors and inflammatory diseases.

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“…Most importantly, our findings suggest that REST-driven modulation of tumor vasculature may contribute to the increased incidence of metastasis and poor survival in patients with SHH-α and SHH-β MBs. ETS1 is a transcription factor and is a known regulator of angiogenic growth factors such as VEGFR1 [44,59,45]. Given the strong correlative parallels in REST and ETS1/CD31/VEGFR1 expression between SHH-MBs and Group 4 MBs, similar mechanisms could be operational in these two subgroups of MBs.…”

Section: Discussionmentioning

confidence: 99%

“…6C,D). The above findings taken in conjunction with VEGFR1 being a known ETS1 target gene, led us to assess whether REST-dependent increase in VEGFR1 expression in DAOY-R cells is mediated by ETS1 [44,45]. Knockdown experiments showed that reduction of ETS1 in DAOY-R cells using two different shRNA-ETS1 constructs did indeed result in a decrease in VEGFR1 levels in these cells (Fig.…”

Section: Rest Elevation Drives Ets1-dependent Increase In Vegfr1 Expressionmentioning

confidence: 99%

REST promotes ETS1‐dependent vascular growth in medulloblastoma

et al. 2021

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Expression of the RE1 ‐silencing transcription factor (REST), a master regulator of neurogenesis, is elevated in medulloblastoma (MB) tumors. A cell‐intrinsic function for REST in MB tumorigenesis is known. However, a role for REST in the regulation of MB tumor microenvironment has not been investigated. Here, we implicate REST in remodeling of the MB vasculature and describe underlying mechanisms. Using REST TG mice, we demonstrate that elevated REST expression in cerebellar granule cell progenitors, the cells of origin of sonic hedgehog (SHH) MBs, increased vascular growth. This was recapitulated in MB xenograft models and validated by transcriptomic analyses of human MB samples. REST upregulation was associated with enhanced secretion of proangiogenic factors. Surprisingly, a REST‐dependent increase in the expression of the proangiogenic transcription factor E26 oncogene homolog 1, and its target gene encoding the vascular endothelial growth factor receptor‐1, was observed in MB cells, which coincided with their localization at the tumor vasculature. These observations were confirmed by RNA‐Seq and microarray analyses of MB cells and SHH‐MB tumors. Thus, our data suggest that REST elevation promotes vascular growth by autocrine and paracrine mechanisms.

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Dihydroartemisinin enhances VEGFR1 expression through up-regulation of ETS-1 transcription factor

Cited by 11 publications

References 50 publications

Autophagy-dependent cell cycle arrest in esophageal cancer cells exposed to dihydroartemisinin

Autophagy-dependent cell cycle arrest in esophageal cancer cells exposed to dihydroartemisinin

Dihydroartemisinin: A Potential Drug for the Treatment of Malignancies and Inflammatory Diseases

REST promotes ETS1‐dependent vascular growth in medulloblastoma

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