Cucurbitacin E inhibits breast tumor metastasis by suppressing cell migration and invasion

Zhang, Tao; Li, Jingjie; Dong, Yujuan; Zhai, Dong; Lai, Li Wen; Dai, Fujun; Deng, Huayun; Chen, Yi Hua; Liu, Mingyao; Yi, Zhengfang

doi:10.1007/s10549-012-2175-5

Cited by 94 publications

(86 citation statements)

References 48 publications

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“…The unanticipated finding that cucurbitacin I activates RhoA in breast cancer cells led us to speculate that the inhibitory effect of this compound on Rac1 activation could be related to an imbalance between the activity of Rac and Rho. Cucurbitacin I and its derivatives are natural terpenoids isolated from plants that have been extensively studied due to their anticancer and anti-inflammatory activities (Chen et al, 2005;Iwanski et al, 2010;Lee et al, 2010), and more recently identified as potent antimetastatic agents in breast cancer (Zhang et al, 2012a) Cucurbitacin B treatment of cancer cells, including breast Tannin-Spitz et al, 2007;Wakimoto et al, 2008;Dakeng et al, 2012). In fact, numerous reports show that cucurbitacin derivatives induce cell cycle arrest, mainly in G 2 /M.…”

Section: Discussionmentioning

confidence: 99%

Cucurbitacin I Inhibits Rac1 Activation in Breast Cancer Cells by a Reactive Oxygen Species-Mediated Mechanism and Independently of Janus Tyrosine Kinase 2 and P-Rex1

López‐Haber

Kazanietz

2013

Mol Pharmacol

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The small GTPase Rac1 has been widely implicated in mammary tumorigenesis and metastasis. Previous studies established that stimulation of ErbB receptors in breast cancer cells activates Rac1 and enhances motility via the Rac-guanine nucleotide exchange factor P-Rex1. As the Janus tyrosine kinase 2 (Jak2)/ signal transducer and activator of transcription 3 (Stat3) pathway has been shown to be functionally associated with ErbB receptors, we asked if this pathway could mediate P-Rex1/Rac1 activation in response to ErbB ligands. Here we found that the anticancer agent cucurbitacin I, a Jak2 inhibitor, reduced the activation of Rac1 and motility in response to the ErbB3 ligand heregulin in breast cancer cells. However, Rac1 activation was not affected by Jak2 or Stat3 RNA interference, suggesting that the effect of cucurbitacin I occurs through a Jak2-independent mechanism. Cucurbitacin I also failed to affect the activation of P-Rex1 by heregulin. Subsequent analysis revealed that cucurbitacin I strongly activates RhoA and the Rho effector Rho kinase (ROCK) in breast cancer cells and induces the formation of stress fibers. Interestingly, disruption of the RhoA-ROCK pathway prevented the inhibitory effect of cucurbitacin I on Rac1 activation by heregulin. Lastly, we found that RhoA activation by cucurbitacin I is mediated by reactive oxygen species (ROS). The ROS scavenger N-acetyl L-cysteine and the mitochondrial antioxidant Mito-TEMPO rescued the inhibitory effect of cucurbitacin I on Rac1 activation. In conclusion, these results indicate that ErbB-driven Rac1 activation in breast cancer cells proceeds independently of the Jak2 pathway. Moreover, they established that the inhibitory effect of cucurbitacin I on Rac1 activity involves the alteration of the balance between Rho and Rac.

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Section: Discussionmentioning

confidence: 99%

Cucurbitacin I Inhibits Rac1 Activation in Breast Cancer Cells by a Reactive Oxygen Species-Mediated Mechanism and Independently of Janus Tyrosine Kinase 2 and P-Rex1

López‐Haber

Kazanietz

2013

Mol Pharmacol

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“…In MDA-MB-231 and 4T1 human breast cancer cells, cucurbitacin E suppresses breast tumor metastasis via inhibition of the Src/FAK/Rac1/MMP pathway (103). In PC3 and HUVEC cells, cucurbitacin E restrains tumor angiogenesis via inhibition of VEGFR2-mediated Jak/ STAT3 and MAPK signaling pathways (104).…”

Section: Steroidmentioning

confidence: 99%

A map describing the association between effective components of traditional Chinese medicine and signaling pathways in cancer cells in vitro and in vivo

Xia

Chen

Zhang

et al. 2014

DD^|^T

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“…And its poor prognosis is always related to invasion and metastasis, which are typical features for breast cancer patients in their advanced tumor progression [2,3]. In a typical metastasis process, tumor cells have to disseminate and intravasate into blood vessels at the primary tumor site, travel through the vascular systems, and then extravasate out from blood vessel to colonialize in the parenchyma of distal tissues.…”

Section: Introductionmentioning

confidence: 99%

Reductions in Myeloid-Derived Suppressor Cells and Lung Metastases using AZD4547 Treatment of a Metastatic Murine Breast Tumor Model

Liu

Han

et al. 2014

Cell Physiol Biochem

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Background: AZD4547, a small-molecule inhibitor targeting the tyrosine kinase of Fibroblast Growth Factor Receptors (FGFRs), is currently under phase II clinical study for human subjects having breast cancer, while the underlying mechanism remains elusive. The aim of this study is to explore the potential mechanism by which AZD4547 inhibits breast tumor lung metastases at the level of the tumor microenvironment. Methods: First, through in vitro experiments, we investigated the efficacy of the FGFRs inhibitor AZD4547 on 4T1 tumor cells for their proliferation, apoptosis, migration, and invasion. Second, by in vivo animal experiments, we evaluated the effects of AZD4547 on tumor growth and lung metastases in 4T1 tumor-bearing mice. Finally, we examined the impact of AZD4547 on the infiltration of myeloid-derived suppressor cells (MDSCs) in lung, spleens, peripheral blood and tumor. Results: Through this study we found that AZD4547 could efficiently suppress tumor 4T1 cells through restraining their proliferation, blocking migration and invasion, and inducing apoptosis in vitro. In animal model we also demonstrated that AZD4547 was able to inhibit tumor growth and lung metastases, consistent with the decreased MDSCs accumulation in the tumor and lung tissues, respectively. Moreover, the reduced number of MDSCs in peripheral blood and spleens were also observed in the AZD4547-treated mice. Importantly, through the AZD4547 treatment, the CD4⁺ and CD8⁺ T-cells were significantly increased in tumor and spleens. Conclusion: Our studies showed that AZD4547 can inhibit breast cancer cell proliferation, induce its apoptosis and block migration and invasion in vitro and suppress tumor growth and lung metastases by modulating the tumor immunologic microenvironment in vivo.

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Cucurbitacin E inhibits breast tumor metastasis by suppressing cell migration and invasion

Cited by 94 publications

References 48 publications

Cucurbitacin I Inhibits Rac1 Activation in Breast Cancer Cells by a Reactive Oxygen Species-Mediated Mechanism and Independently of Janus Tyrosine Kinase 2 and P-Rex1

Cucurbitacin I Inhibits Rac1 Activation in Breast Cancer Cells by a Reactive Oxygen Species-Mediated Mechanism and Independently of Janus Tyrosine Kinase 2 and P-Rex1

A map describing the association between effective components of traditional Chinese medicine and signaling pathways in cancer cells in vitro and in vivo

Reductions in Myeloid-Derived Suppressor Cells and Lung Metastases using AZD4547 Treatment of a Metastatic Murine Breast Tumor Model

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