Abstract
Praeruptorin A (PA) is a pyranocumarin present in the dried root of Peucedanumpraeruptorum Dunn that has anticancer effects against several types of cells. However, the effect of PA on human cervical cancer cells is unknown. Our results indicate that PA significantly inhibited cell proliferation, colony formation, migration, invasion, and wound closure of HeLa and SiHa cells, induced cell cycle arrest at G0/G1 phase, upregulated Rb, p16, p21 and p27 proteins and downregulated cyclin D1 and S-phase kinase-associated protein 2 (Skp2) proteins. PA also significantly reduced expression of matrix metalloproteinase-2 (MMP-2) and increased expression of tissue inhibitor of metalloproteinase-2 (TIMP-2). In addition, PA suppressed ERK1/2 activation and increased the effect of PD98059 (a specific MEK1/2 inhibitor) in downregulation of MMP-2 and upregulation of TIMP-2. PA treatment inhibited the effect of 12-O-tetradecanoylphorbol-13-acetate (TPA) on upregulation of ERK1/2 activation, MMP-2 expression, cellular migration, and invasion of HeLa cells. Our findings are the first to demonstrate the activity of PA against cervical cancer cells, and suggest this agent has promise as a therapeutic agent in treatment of human cervical cancer.
Highlights
Cervical cancer is the second most common gynecologic cancer worldwide, and there were 530,000 new diagnoses in 2012 and 300,000 deaths in 2015
The results showed that the protein and mRNA levels of matrix metalloproteinase-2 (MMP-2) were significantly reduced and those of tissue inhibitor of metalloproteinase-2 (TIMP-2) were significantly elevated at Praeruptorin A (PA) concentrations of 20 and
To further confirm the role of MMP-2 in inhibiting PA effects, we demonstrate that MMP-2 inhibition with an antibody (MMP-2 Ab) against MMP-2 decreased the mobility (Figure 4A), migration and invasion (Figure 4B) of HeLa cells compared with goat IgG antibody, and these effects were more marked in cells co-treated with both PA and MMP-2 antibody (Figure 4A,B), but no affect in cell growth (Figure 4C)
Summary
Cervical cancer is the second most common gynecologic cancer worldwide, and there were 530,000 new diagnoses in 2012 and 300,000 deaths in 2015. MMP-2 and MMP-9 have important roles in the development of malignant cervical cancer in animal models and humans [8,9] Several endogenous inhibitors, such as tissue inhibitor of metalloproteinase (TIMPs), regulate MMP through modification of its activity and stability [10]. Western blotting of proteins with critical roles in cell cycle regulation indicated that PA treatment led to a concentration-dependent reductions in the levels of cyclin D1 and Skp, but increased levels of p21, p27, Rb, and p16 We investigated the effect of PA on the growth, migration, and invasion, of human cervical cancer (HeLa and SiHa) cells and the molecular mechanisms of these effects. Our results suggest that PA inhibits the proliferation and invasion of human cervical cancer cells by disruption of ERK1/2 signaling
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