Abstract
BackgroundDeregulated ErbB signaling plays an important role in tumorigenesis of pancreatic cancer. However, patients with pancreatic cancer benefit little from current existed therapies targeting the ErbB signaling. Here, we explore the potential anti-tumor activity of Valproic acid against pancreatic cancer via targeting ErbB family members.MethodsCell viability assay and apoptosis evaluation were carried out to determine the efficacy of VPA on pancreatic cancer cells. Western blot analyses were performed to determine the expression and activation of proteins. Apoptosis enzyme-linked immunosorbent assay was used to quantify cytoplasmic histone associated DNA fragments. Lentiviral expression system was used to introduce overexpression of exogeneous genes or gene-targeting short hairpin RNAs (shRNAs). qRT-PCR was carried out to analyze the mRNAs and miRNAs expression levels. Tumor xenograft model was established to evaluate the in vivo anti-pancreatic cancer activity of VPA.ResultsVPA preferentially inhibited cell proliferation/survival of, and induced apoptosis in EGFR/ErbB2/ErbB3-coexpressing pancreatic cancer cells within its clinically achievable range [40~100 mg/L (0.24~0.6 mmol/L)]. Mechanistic investigations revealed that VPA treatment resulted in simultaneous significant down-regulation of EGFR, ErbB2, and ErbB3 in pancreatic cancer cells likely via induction of ErbB family members-targeting microRNAs. Moreover, the anti-pancreatic cancer activity of VPA was further validated in tumor xenograft model.ConclusionsOur data strongly suggest that VPA may be added to the treatment regimens for pancreatic cancer patients with co-overexpression of the ErbB family members.
Highlights
Deregulated Erythroblastic leukemia viral oncogene homolog (ErbB) signaling plays an important role in tumorigenesis of pancreatic cancer
Valproic acid (VPA) preferentially inhibits cell proliferation/survival of Epidermal growth factor receptor (EGFR)/ErbB2/ErbB3-coexpressing pancreatic cancer cells in vitro To explore whether VPA might show any therapeutic effect on pancreatic cancer, we investigated its anti-proliferative/
In an effort to investigate the underlying mechanism, we found that while the expression of cyclin-dependent kinase (CDK) inhibitor P21, one of the most commonly induced genes by Histone deacetylases (HDACs) inhibitor (HDACi) [29], Fig. 1 VPA selectively inhibits proliferation/survival of EGFR/ErbB2/ErbB3-coexpressing pancreatic cancer cells. a Western blotting analysis of the expression of EGFR, ErbB2, and ErbB3 in pancreatic cancer cells. b Human pancreatic cancer cells were plated onto 96-well plates with complete culture medium (RPMI1640, 10% fetal bovine serum (FBS))
Summary
Deregulated ErbB signaling plays an important role in tumorigenesis of pancreatic cancer. Genetic studies have revealed that during the progression of three broad stages of pancreatic cancer, acquired somatic mutations in oncogenes and tumor suppressor genes accumulate and account for initiation and aggressive development of this malignant disease. These mutations occur most frequently in KRAS, CDKN2A, TP53 and SMAD4 [8,9,10]. Among all subfamilies of RTKs, the ErbB family members consisting of the epidermal growth factor receptor EGFR (ErbB1), HER2 (ErbB2), HER3 (ErbB3), and HER4 (ErbB4) play important role in the initiation and maintenance of a variety of human cancers, including pancreatic cancer [14, 15]. Deregulated RTKs/ RAS/RAF/MEK/MAPK signaling pathway is undoubtedly important for pancreatic cancer biology, and extensive efforts have been taken to target this pathway for systemic therapy [17,18,19,20]
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