Title:Ligustrazine Suppresses the Growth of HRPC Cells through the Inhibition of Cap- Dependent Translation Via Both the mTOR and the MEK/ERK Pathways
Volume: 15
Issue: 6
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 and Xiang Xu
Affiliation:
Keywords:
Cap-dependent translation, HRPC, MEK/ERK, mTOR, Ligustrazine.
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.
