Osthole inhibits the PI3K/AKT signaling pathway via activation of PTEN and induces cell cycle arrest and apoptosis in esophageal squamous cell carcinoma
Introduction
Esophageal cancer is the third most prevalent cancer and the fourth leading cause of cancer death in China, with esophageal squamous cell carcinoma (ESCC) accounting for over 90% of the cases [1,2]. Despite advances in diagnosis and therapy of patients with esophageal cancer, overall five-year survival rate only ranges from 15% to 25% [3]. In order to ameliorate the survival rate, efforts have been made to explore novel anticancer agents, and much attention has been focused on traditional Chinese herbal medicines, due to their wide variety of biological activities as well as low levels of side effects and toxicity [[4], [5], [6]].
Osthole (chemical formula C15H16O3) is an active component extracted from the fruit of Fructus Cnidii, which has long been applied in traditional Chinese medicine to cure impotence, lumbar pain and rheumatic pain [7,8]. In previous reports, osthole has been demonstrated to possess vasorelaxant [9], anti-osteoporotic [10], anti-inflammatory properties [11,12], and to exert anti-allergic [13] and anti-seizure effects [14]. Recently, increasing evidence suggests that osthole has antitumor activity by inducing apoptosis and inhibiting cancer cell growth and metastasis [[15], [16], [17]]. However, the effect of osthole on human ESCC cells and its underlying mechanism have not been reported yet.
In this study, we demonstrated that osthole remarkably inhibited ESCC cell proliferation in dose-and time-dependent manner, and induce G2/M phase arrest and apoptosis of ESCC cells. Moreover, PTEN-PI3K/AKT signaling pathway can be modulated by osthole treatment. Thus, osthole might be a novel active component to exploit an effective medicine for treatment of ESCC patients.
Section snippets
Reagents, antibodies and kits
Osthole (>98%) powder was obtained from Chengdu Must Bio-Technology Co., Ltd. (Lot No. MUST-16012417; Sichuan, China) and then dissolved in dimethyl sulfoxide (DMSO). Antibodies against Cyclin B1, Cdc2, BAX, Bcl-2, PARP1, Survivin, PTEN, PI3K, total AKT and GAPDH were all purchased from Proteintech Group, Inc. (Chicago, IL, USA). Antibody against cleaved Caspase3, cleaved Caspase9 and phosphorylated AKT (p-AKT) (ser473) was obtained from Cell Signaling Technology (Danvers, MA, USA). Antibody
Osthole inhibits the proliferation of ESCC cells
The chemical structure of osthole is shown in Fig. 1A. To explore the effect of osthole on ESCC cell proliferation, five ESCC cell lines (KYSE30, KYSE150, KYSE180, KYSE410 and KYSE450) were employed and treated with osthole in different concentrations (0, 20, 40, 80, 120, 160, 200 or 240 μM) for 24 or 48 h. Cell viability was examined using CCK-8 assay for each indicated concentration and time point. As expected, osthole treatment led to reduced viability of ESCC cell in a dose-and
Discussion
Limited clinical approach for treatment remains a major challenge for the patients with ESCC. Increasing evidence suggests that natural agents may represent a new avenue for the development of successful cancer treatments [19]. Such agents have also shown promise in ESCC [20,21]. Osthole, an active compound derived from Fructus Cnidii, has been found widespread application as an anti-inflammatory, anti-allergic, and anti-seizure agent [[11], [12], [13], [14]]. Moreover, both in vitro and in
Acknowledgements
This work was supported by National Natural Science Foundation of China (81402283) and Natural Science Foundation of Liaoning (2015020304).
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