Abstract
Pancreatic cancer has a high mortality rate due to poor rates of early diagnosis. One tumor suppressor gene in particular, p53, is frequently mutated in pancreatic cancer, and mutations in p53 can inactivate normal wild type p53 activity and increase expression of transcription factor forkhead box M1 (FoxM1). Overexpression of FoxM1 accelerates cellular proliferation and cancer progression. Therefore, inhibition of FoxM1 represents a therapeutic strategy for treating pancreatic cancer. Broussoflavonol B (BF-B), isolated from the stem bark of Broussonetia kazinoki Siebold has previously been shown to inhibit the growth of breast cancer cells. This study aimed to investigate whether BF-B exhibits anti-pancreatic cancer activity and if so, identify the underlying mechanism. BF-B reduced cell proliferation, induced cell cycle arrest, and inhibited cell migration and invasion of human pancreatic cancer PANC-1 cells (p53 mutated). Interestingly, BF-B down-regulated FoxM1 expression at both the mRNA and protein level. It also suppressed the expression of FoxM1 downstream target genes, such as cyclin D1, cyclin B1, and survivin. Cell cycle analysis showed that BF-B induced the arrest of G0/G1 phase. BF-B reduced the phosphorylation of extracellular signal-regulated kinase ½ (ERK½) and expression of ERK½ downstream effector c-Myc, which regulates cell proliferation. Furthermore, BF-B inhibited cell migration and invasion, which are downstream functional properties of FoxM1. These results suggested that BF-B could repress pancreatic cancer cell proliferation by inactivation of the ERK/c-Myc/FoxM1 signaling pathway. Broussoflavonol B from Broussonetia kazinoki Siebold may represent a novel chemo-therapeutic agent for pancreatic cancer.
Highlights
Pancreatic cancer is one of the most lethal human malignancies with a five-year survival rate of around 9% [1]
BF-B inhibited cell migration and invasion, which are downstream functional properties of forkhead box M1 (FoxM1). These results suggested that BF-B could repress pancreatic cancer cell proliferation by inactivation of the ERK/c-Myc/FoxM1 signaling pathway
SeveralSeveral prenylated flavonoids from plantswere were reported to exhibit cytotoxic onSeveral different cancer cellflavonoids types [23,24], and a metabolite of flavonoids was recently suggested the prenylated from medicinal plants were reported to exhibit cytotoxicasactivity on different cancer cell types [23,24], and a metabolite of flavonoids was recently suggested as the cyclin dependent kinase
Summary
Pancreatic cancer is one of the most lethal human malignancies with a five-year survival rate of around 9% [1]. An urgent need exists to develop new drugs for treating pancreatic cancer. 70% of pancreatic cancers have p53 gene mutations [3,4] and most p53 mutations directly disrupt the protein’s DNA-binding activity [5]. Inactivation of wild-type p53 by loss or mutation of the p53 gene leads to chemotherapy resistance, reduces metabolic regulation, and increases metastasis [6]. FoxM1 is an oncogenic transcription factor that plays important roles in the initiation, progression, metastasis, and drug resistance of a variety of human tumors, including pancreatic cancer [9,10].
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