A novel synthetic Asiatic acid derivative induces apoptosis and inhibits proliferation and mobility of gastric cancer cells by suppressing STAT3 signaling pathway

Abstract

Activation of the transcription factor, signal transducers and activators of transcription 3 (STAT3), has been linked to the proliferation and migration of a variety of human cancer cells. These actions occur via the upregulation or downregulation of cell survival and tumor suppressor genes, respectively. Importantly, agents that can suppress STAT3 activation have the potential for use in the prevention and treatment of various cancers. In this study, an Asiatic acid (AA) derivative, N-(2α,3β,23-acetoxyurs-12-en-28-oyl)-l-proline methyl ester (AA-PMe), is reported to dose dependently suppress constitutive STAT3 activation in gastric cancer cells. This inhibition was mediated by blockade of Janus-activated kinase 2. Additionally, AA-PMe regulated the expression of STAT3-modulated gene products, including cyclin D1, Bax, Bcl-2, c-Myc, and matrix metalloproteinase (MMP)-2 and MMP-9. Finally, transfection with both a STAT3 mimic and an inhibitor reversed the AA-PMe-driven modulation of STAT3 downstream gene products. Overall, these results suggest that AA-PMe is a novel blocker of STAT3 activation and has the potential for the prevention and treatment of gastric cancer.

Asiatic Acid, Extracted from Centella asiatica and Induces Apoptosis Pathway through the Phosphorylation p38 Mitogen-Activated Protein Kinase in Cisplatin-Resistant Nasopharyngeal Carcinoma Cells

“…It has been proposed that Asiatic acid has various pharmacological activities such as anti-inflammatory and antioxidant, as well as the potent anti-hypertensive, neuro and cardio-protective, antimicrobial, and antitumor activities [5]. Many studies had proved the anti-cancer effects in vitro or in vivo of AA in breast cancer, ovary cancer, colon cancer, gastric cancer, cholangiocarcinoma, glioblastoma, lung cancer, lymphoma, and melanoma [6,[11][12][13][14][15][16][17][18]. Our study corresponds with these researches and revealed the anti-cancer effect of AA in both dose and time dependent manners in cisplatin-resistance NPC cell lines (Figure 1b).…”

Carbon Ion Therapy Inhibits Esophageal Squamous Cell Carcinoma Metastasis by Upregulating STAT3 Through the JAK2/STAT3 Signaling Pathway

“…It has been shown that STAT3 protein binds to a highaffinity binding site in the promoter region of the MMP2 gene, which upregulates MMP2 expression. Inhibition of STAT3 inhibits its target gene MMP2 and inhibits tumor cell invasion (33). In malignant tumors, E-cadherin, an epithelial marker, is downregulated, and vimentin, an interstitial marker, is upregulated; moreover, cell adhesion is decreased, migration is enhanced, and tumor cells are more susceptible to invasion and metastasis (34).…”

VGLL4 interacts with STAT3 to function as a tumor suppressor in triple-negative breast cancer

“…This suggests that VGLL4 may interact with STAT3, and further CoIP experiments confirmed that VGLL4 has a protein–protein interaction with STAT3. It has been reported that MMP2, MMP-9, Cyclin D1, Cyclin E1, and Bcl-2 are downstream of STAT3 transcriptional regulation 38–40 , and STAT3 is primarily activated by its protein phosphorylation and then activates downstream transcription 33 . By inhibiting and overexpressing VGLL4, we found that phospho-STAT3, Cyclin D1 and Bcl-2, downstream targets of STAT3, were elevated and inhibited, respectively.…”