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Kaempferol inhibits cell proliferation and glycolysis in esophagus squamous cell carcinoma via targeting EGFR signaling pathway

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Tumor Biology

Abstract

Antitumor activity of kaempferol has been studied in various tumor types, but its potency in esophagus squamous cell carcinoma is rarely known. Here, we reported the activity of kaempferol against esophagus squamous cell carcinoma as well as its antitumor mechanisms. Results of cell proliferation and colony formation assay showed that kaempferol substantially inhibited tumor cell proliferation and clone formation in vitro. Flow cytometric analysis demonstrated that tumor cells were induced G0/G1 phase arrest after kaempferol treatment, and the expression of protein involved in cell cycle regulation was dramatically changed. Except the potency on cell proliferation, we also discovered that kaempferol had a significant inhibitory effect against tumor glycolysis. With the downregulation of hexokinase-2, glucose uptake and lactate production in tumor cells were dramatically declined. Mechanism studies revealed kaempferol had a direct effect on epidermal growth factor receptor (EGFR) activity, and along with the inhibition of EGFR, its downstream signaling pathways were also markedly suppressed. Further investigations found that exogenous overexpression of EGFR in tumor cells substantially attenuated glycolysis suppression induced by kaempferol, which implied that EGFR also played an important role in kaempferol-mediated glycolysis inhibition. Finally, the antitumor activity of kaempferol was validated in xenograft model and kaempferol prominently restrained tumor growth in vivo. Meanwhile, dramatic decrease of EGFR activity and hexokinase-2 expression were observed in kaempferol-treated tumor tissue, which confirmed these findings in vitro. Briefly, these studies suggested that kaempferol, or its analogues, may serve as effective candidates for esophagus squamous cell carcinoma management.

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Acknowledgments

This work was funded by the National Natural Science Foundation of China (81301829) and the Key Project of Science and Technology Commission of Shanghai Municipality (15411951700).

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    Authors and Affiliations

    1. Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiaotong University, No. 241 West Huaihai Road, Shanghai, 200030, China

      Shihua Yao & Wentao Fang

    2. Department of Thoracic Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China

      Shihua Yao, Xiaowei Wang, Chunguang Li, Tiejun Zhao & Hai Jin

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    1. Shihua Yao
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    Correspondence to Wentao Fang.

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    Shihua Yao and Xiaowei Wang contributed equally to this work.

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    Yao, S., Wang, X., Li, C. et al. Kaempferol inhibits cell proliferation and glycolysis in esophagus squamous cell carcinoma via targeting EGFR signaling pathway. Tumor Biol. 37, 10247–10256 (2016). https://doi.org/10.1007/s13277-016-4912-6

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    • DOI: https://doi.org/10.1007/s13277-016-4912-6

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