FoxM a downstream target of Gli has been mainly related

FoxM1, a downstream target of Gli, has been mainly related to 71 8 regulation and cellular proliferation in tumor (Alvarez-Fernandez and Medema, 2013, Halasi and Gartel, 2013, Teh et al., 2002). Especially, FoxM1 is a regulator of G1/S and G2/M transitions and M-phase progression (Wonsey & Follettie, 2005). It controls cell cycle-related molecules such as c-Myc (Wierstra & Alves, 2006), cyclin B1 (Leung et al., 2001) and survivin (Nestal de Moraes et al., 2015). c-Myc, an oncoprotein, is responsible for cellular proliferation and cell cycle regulation of cancer cells. c-Myc expression is elevated and deregulated in neoplastic cells (Albihn et al., 2010, DePinho et al., 1991). Cyclin B1, another target of FoxM1, is usually expressed at very low levels. It accumulates sharply only at G2/M cell cycle transition under normal conditions. In cancer cells, cyclin B1 is overexpressed throughout cell cycle progression (Ye, Wang, Wu, Li, & Chai, 2017). Survivin, an anti-apoptotic protein, plays a role in the regulation of cell division and spindle formation. It is essential for cell cycle progression (Mita, Mita, Nawrocki, & Giles, 2008). Overexpression of survivin is frequently associated with poor prognosis and drug resistance in neoplastic mammary cells (Hinnis, Luckett, & Walker, 2007). As shown in Fig. 3, Z-ajoene suppressed target gene expression of FoxM1, c-Myc, cyclin B1, and survivin, together with depressed proliferation of PANC-1 pancreatic cancer cells (Fig. 4A). These results are in agreement with down-regulation of FoxM1 by Z-ajoene through inhibition of Gli activation. Furthermore, cell cycle analysis demonstrated that Z-ajoene significantly elevated the percentage of G2/M phase cells (Fig. 4B). These results suggest that Z-ajoene can reduce the proliferation of PANC-1 pancreatic cancer cells through inducing cell cycle arrest in G2/M phase. Taken together, Z-ajoene exhibits anti-proliferative activity in pancreatic cancer cells by down-regulating Gli in aberrantly activated Hh signaling pathway. Therefore, inhibition of Gli is a well-organized approach to regulate the Hh signaling pathway for cancer therapy.
Conclusion
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Conflict of interest
Acknowledgements This study was supported by the National Research Foundation of Korea (NRF) Grant funded by the Korean Government (MSIP) (Nos. 2011-0030074 and 2018R1D1A3B07050361) and Sookmyung Women’s University Specialization Program Funding.
Introduction Cystic fibrosis (CF), an autosomal recessive genetic disease that mostly occurs in Caucasians [1], is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes a cAMP-regulated anion channel at the apical membrane of epithelial cells of various organs [2]. Although more than 2000 mutations have been identified in CF (http://www.genet.sickkids.on.ca/cftr/app), deletion of phenylalanine at 508 (ΔF508), which results in a CFTR-folding defect and endoplasmic reticulum-associated degradation, is the most frequent mutation occurring in >80% of CF patients [3,4]. CFTR mutations affect mucosal physiology of the respiratory, digestive, and reproductive tracts, leading to different clinical manifestations including pancreatic insufficiency, focal biliary cirrhosis, infertility, and chronic airway obstruction [5]. Particularly, there has been recent interest in the risk of various cancers in CF patients and CFTR mutation carriers [[6], [7], [8]]. For example, a study involving >38,000 CF patients revealed increased incidence of digestive tract cancers including colorectal cancer [9]. Interestingly, CFTR is frequently hypermethylated in various cancer cell lines and clinical tumor samples [10,11], indicating that its loss might be critical for the pathogenesis of cancer. Moreover, epithelial cell proliferation was found to increase in the intestines of CFTR-mutant mice [12]. However, the exact mechanisms underlying this effect remains elusive.