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