Valproic acid activates notch-1 signaling and regulates the neuroendocrine phenotype in carcinoid cancer cells

被引:131
作者
Greenblatt, David Yu
Vaccaro, Abram M.
Jaskula-Sztul, Renata
Ning, Li
Haymart, Megan
Kunnimalaiyaan, Muthusamy
Chen, Herbert
机构
[1] Univ Wisconsin, Dept Surg, Endocrine Surg Res Labs, Madison, WI USA
[2] Univ Wisconsin, Paul P Carbone Comprehens Canc Ctr, Madison, WI USA
关键词
valproic acid; carcinoid tumors; neuroendocrine tumors; Notch-1; achaete scute complex like 1 (ASCL1);
D O I
10.1634/theoncologist.12-8-942
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Carcinoid tumors are neuroendocrine malignancies that frequently metastasize and secrete hormones that cause debilitating symptoms in patients. In this study we report the effects of valproic acid (VPA), a drug long used for the treatment of epilepsy, on the growth and neuroendocrine phenotype of human carcinoid cancer cells. VPA treatment of gastrointestinal and pulmonary carcinoid cells resulted in a dose-dependent inhibition of cancer cell growth. Western blot analysis revealed degradation of cyclin D1 and an increase in cyclin-dependent kinases p21 and p27 with VPA treatment. Flow cytometry confirmed that the mechanism of VPA-induced growth inhibition is G1 phase cell cycle arrest. Furthermore, VPA suppressed expression of the neuroendocrine tumor marker chromogranin A. In addition to these effects, VPA also increased levels of full-length Notch-1 and the active Notch-1 intracellular domain. Luciferase reporter assays incorporating the centromere-binding factor 1 (CBF-1) binding site and the achaete-scute complex-like 1 (ASCL-1) promoter confirmed the functional activity of VPA-induced Notch-1. Transfection of Notch-1 small-interfering RNA into carcinoid tumor cells blocked the effects of VPA on Notch-1 activation, ASCL-1 suppression, p21 induction, and cell growth inhibition. VPA also suppressed growth of carcinoid tumors in vivo in a mouse tumor xenograft experiment. These findings confirm the important role of Notch-1 in regulating the growth and neuroendocrine phenotype of carcinoid tumor cells. On the basis of this study, a clinical trial of VPA for patients with advanced carcinoid cancer will be conducted.
引用
收藏
页码:942 / 951
页数:10
相关论文
共 52 条
[1]   Notch signaling in cancer [J].
Allenspach, EJ ;
Maillard, I ;
Aster, JC ;
Pear, WS .
CANCER BIOLOGY & THERAPY, 2002, 1 (05) :466-476
[2]   Notch signaling: Cell fate control and signal integration in development [J].
Artavanis-Tsakonas, S ;
Rand, MD ;
Lake, RJ .
SCIENCE, 1999, 284 (5415) :770-776
[3]   Antiproliferative and proapoptotic effects of histone deacetylase inhibitors on gastrointestinal neuroendocrine tumor cells [J].
Baradari, Viola ;
Huether, Alexander ;
Hoepfner, Michael ;
Schuppan, Detlef ;
Scheruebl, Hans .
ENDOCRINE-RELATED CANCER, 2006, 13 (04) :1237-1250
[4]   Notch signalling: a simple pathway becomes complex [J].
Bray, Sarah J. .
NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2006, 7 (09) :678-689
[5]   Valproic acid induces apoptosis and cell cycle arrest in poorly differentiated thyroid cancer cells [J].
Catalano, MG ;
Fortunati, N ;
Pugliese, M ;
Costantino, L ;
Poli, R ;
Bosco, O ;
Boccuzzi, G .
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 2005, 90 (03) :1383-1389
[6]   Antineoplastic effects of the DNA methylation inhibitor hydralazine and the histone deacetylase inhibitor valproic acid in cancer cell lines [J].
Chavez-Blanco, Alma ;
Perez-Plasencia, Carlos ;
Perez-Cardenas, Enrique ;
Carrasco-Legleu, Claudia ;
Rangel-Lopez, Edgar ;
Segura-Pacheco, Blanca ;
Taja-Chayeb, Lucia ;
Trejo-Becerril, Catalina ;
Gonzalez-Fierro, Aurora ;
Candelaria, Myrna ;
Cabrera, Gustavo ;
Duenas-Gonzalez, Alfonso .
CANCER CELL INTERNATIONAL, 2006, 6 (1)
[7]   The mood-stabilizing agent valproate inhibits the activity of glycogen synthase kinase-3 [J].
Chen, G ;
Huang, LD ;
Jiang, YM ;
Manji, HK .
JOURNAL OF NEUROCHEMISTRY, 1999, 72 (03) :1327-1330
[8]  
Chen H, 1997, CELL GROWTH DIFFER, V8, P677
[9]   Conservation of the Drosophila lateral inhibition pathway in human lung cancer: A hairy-related protein (HES-1) directly represses achaete-scute homolog-1 expression [J].
Chen, H ;
Thiagalingam, A ;
Chopra, H ;
Borges, MW ;
Feder, JN ;
Nelkin, BD ;
Baylin, SB ;
Ball, DW .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1997, 94 (10) :5355-5360
[10]   Valproic acid and butyrate induce apoptosis in human cancer cells through inhibition of gene expression of Akt/protein kinase B [J].
Chen, Jihong ;
Ghazawi, Feras M. ;
Bakkar, Wafae ;
Li, Qiao .
MOLECULAR CANCER, 2006, 5 (1)