Ligustrazine Suppresses the Growth of HRPC Cells through the Inhibition of Cap- Dependent Translation Via Both the mTOR and the MEK/ERK Pathways

Author(s): Jiaoyan Han, Jiao Song, Xiangyun Li, Ming Zhu, Wei Guo, Wei Xing, Rongshen Zhao, Xiao He, Xiaoping Liu, Shali Wang, Yunyun Li, Hong Huang, Xiang Xu

Journal Name: Anti-Cancer Agents in Medicinal Chemistry
(Formerly Current Medicinal Chemistry - Anti-Cancer Agents)

Volume 15 , Issue 6 , 2015

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Graphical Abstract:


Ligustrazine (TMP) has recently been used for the treatment of various cancers. However, its exact mechanisms of action, particularly the functions and the mechanisms of Ligustrazine in human hormone-refractory prostate cancer (HRPC), have not yet been extensively studied. Recently, our findings suggest that Ligustrazine dose- and time-dependently inhibits the growth of HRPC cells by reducing their proliferation and promoting apoptosis. Interestingly, the treatment of hormone-refractory prostate cancer (PC-3) cells with Ligustrazine results in a significant inhibition of the activation of mTOR and related downstream targets, which are critical for cell growth. Furthermore, pull-down assays with 7-methyl- GTP Sepharose 4B beads indicate that Ligustrazine reduces the available eIF4E for translation initiation. Accordingly, the results from the translation assay using a luciferase reporter system further demonstrate that Ligustrazine indeed inhibits cap-dependent translation. In addition, the transient overexpression of eIF4E or MNK1 prevents the Ligustrazine-induced inhibition of proliferation and confers significant protection against Ligustrazine-induced apoptosis. Therefore, the present study provides evidences that Ligustrazine may be a candidate for therapeutic reagent for the treatment of HRPC and certifies that Ligustrazine modulates the availability of eIF4E mainly through the mTOR and MEK/ERK signaling pathways to inhibit cap-dependent translation. Taken together, our results indicate that the inhibition of cap-dependent translation is likely an essential mechanism in Ligustrazine-induced apoptosis.

Keywords: Cap-dependent translation, HRPC, MEK/ERK, mTOR, Ligustrazine.

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Article Details

Year: 2015
Page: [764 - 772]
Pages: 9
DOI: 10.2174/1871520615666150305112120
Price: $65

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