Journal
ANNALS OF SURGERY
Volume 247, Issue 6, Pages 1036-1040Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/SLA.0b013e3181758d0e
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Funding
- NCI NIH HHS [R01 CA109053-01A2, R01 CA109053-02, CA109053, R01 CA109053-04, R01 CA109053, T32 CA090217-10, T32 CA090217-09, R01 CA109053-03, R01 CA109053-05, T32 CA090217, T32 CA090217-08] Funding Source: Medline
- NIDDK NIH HHS [T35 DK062709, R21 DK064735-02, R21 DK066169, DK066169, R21 DK066169-02, R21 DK066169-01, R21 DK064735, DK064735, R21 DK064735-01] Funding Source: Medline
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Objective: To examine the effects of valproic acid (VPA) on Notch1 expression and cancer cell proliferation in medullary thyroid cancer (MTC) cells. Background: Other than surgery, there are no effective treatments for MTC, a neuroendocrine malignancy that frequently metastasizes. We have previously shown that over-expression of Notch1 in MTC cells inhibits cell growth and hormone production. VPA, a drug long used for the treatment of epilepsy, has recently been identified as a potential Notch1 activator. We hypothesized that VPA might activate Notch1 signaling in MTC cells, with antiproliferative effects. Methods: Human MTC cells were treated with VPA (0-5 mM) and Western blotting was performed to measure levels of Notch1 paths way proteins and neuroendocrine tumor markers. After confirming that VPA is a Notch1 activator in MTC cells, we performed cell proliferation assay. Finally, to determine the mechanism of growth inhibition, we measured protein levels of various markers of apoptosis. Results: Notch1 was absent in MTC cells at baseline. VPA treatment resulted in an increase in both full-length and active Notch1 protein. Notch1 activation with VPA suppressed 2 neuroendocrine tumor markers, ASCL1 and chromogranin A. Importantly, VPA inhibited the growth of MTC cells in a dose-dependent manner. Immunoblot analysis demonstrated caspase activation and poly(ADP-ribose) polymerase cleavage, indicating the induction of apoptosis. Conclusions: VPA activates Notch1 signaling in MTC cells and inhibits their growth by inducing apoptosis. As the safety of VPA in human beings is well established, a clinical trial using this drug to treat patients with advanced MTC could be initiated in the near future.
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