title: Aspirin may inhibit angiogenesis and induce autophagy by inhibiting mTOR signaling pathway in murine hepatocarcinoma and sarcoma models.
abstract: Aspirin is known to have inhibitory effects on growth development in various types of tumor. In previous studies, it was observed to inhibit angiogenesis by downregulating the expression of vascular endothelial growth factor-A (VEGF-A). In the present study, murine H22hepatocarcinoma and S180 sarcoma models were used to ascertain whether aspirin could inhibit angiogenesis and promote autophagy in tumors. Tumor-bearing mice were randomly divided into four groups with 10 mice per group: i) no treatment; ii) low-dose aspirin (100 mg/kg); iii) high-dose aspirin (400 mg/kg); iv) everolimus group (4 mg/kg). The effects of high-dose aspirin were validated through preliminary experiments. The drug treatment was administered every day for 14 days. The tumor size was measured every other day and then the tumor growth curve was plotted, and the tumor inhibitory rates were calculated. The expression levels of phosphorylated mammalian target of rapamycin (p-mTOR), hypoxia-inducible factor-1α (HIF-1α), VEGF-A, UNC-51-like kinase-1 (ULK1) and microtubule-associated protein 1 light chain 3A (LC3A) were detected by immunohistochemistry and western blot analysis, respectively. We observed that tumor growth delay was achieved in both H22hepatocarcinoma and S180 sarcoma models following treatment with aspirin. The tumor growth inhibition rates induced by low and high-dose aspirin and everolimus were 19.6, 33.6 and 53.7% (P<0.05) in H22hepatocarcinoma, and 25.7, 40.6 and 48.7% (P<0.05) in S180 sarcoma. The immunohistochemistry and western blot analysis data from the models revealed that the expression of p-mTOR, HIF-1α and VEGF-A was decreased, while the expression of ULK1 and LC3A was increased following treatment with aspirin and everolimus. The changes were more apparent in the high-dose aspirin and everolimus groups (P<0.01). The inhibitory action of aspirin and everolimus on tumor angiogenesis may be through inhibiting the expression of p-mTOR, HIF-1α and VEGF-A. Alternatively, aspirin may induce autophagy by inhibiting the mTOR signaling target and then increasing ULK1 and LC3A.
authors.affiliation: Key Laboratory for Modern Medicine and Technology of Shandong, Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jinan, Shandong 250062, P.R. China; School of Medicine and Life Sciences, University of Jinan, Shandong Academy of Medical Sciences, Jinan, Shandong 250062, P.R. China.
authors.forename: Qianqian
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: Key Laboratory for Modern Medicine and Technology of Shandong, Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jinan, Shandong 250062, P.R. China.
authors.forename: Zhaopeng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Key Laboratory for Modern Medicine and Technology of Shandong, Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jinan, Shandong 250062, P.R. China.
authors.forename: Zhaoxia
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Latner Thoracic Surgery Research Laboratories and Division of Thoracic Surgery, Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON M5G 1L7, Canada.
authors.forename: Licun
authors.initials: L
authors.lastname: Wu
authors.affiliation: Key Laboratory for Modern Medicine and Technology of Shandong, Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jinan, Shandong 250062, P.R. China.
authors.forename: Weidong
authors.initials: W
authors.lastname: Zhang
keywords: angiogenesis; aspirin; autophagy; mammalian target of rapamycin; tumor