Faculty Collaboration Database

Valproic acid activates Notch1 signaling and induces apoptosis in medullary thyroid cancer cells. Ann Surg 2008 Jun;247(6):1036-40

Date

06/04/2008

Pubmed ID

18520232

Pubmed Central ID

PMC2904809

DOI

10.1097/SLA.0b013e3181758d0e

Scopus ID

2-s2.0-44449130087 (requires institutional sign-in at Scopus site)   69 Citations

Abstract

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 pathway 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.

Author List

Greenblatt DY, Cayo MA, Adler JT, Ning L, Haymart MR, Kunnimalaiyaan M, Chen H

MESH terms used to index this publication - Major topics in bold

Analysis of Variance
Antineoplastic Agents
Apoptosis
Biomarkers, Tumor
Blotting, Western
Carcinoma, Medullary
Down-Regulation
Enzyme-Linked Immunosorbent Assay
Humans
Receptor, Notch1
Signal Transduction
Thyroid Neoplasms
Tumor Cells, Cultured
Valproic Acid