Upregulation of RASSF1A in Colon Cancer by Suppression of Angiogenesis Signaling and Akt Activation
JournalCellular Physiology and Biochemistry
PublisherS. Karger AG
MetadataShow full item record
AbstractBackground/Aims: Silencing of tumor suppressor genes (TSGs) and promotion of angiogenesis are associated with tumor development and metastasis. However, little is known if angiogenic molecules directly control TSGs and vice versa. Methods: A regulatory link between angiogenesis and down regulation of TSGs was evaluated using an anti-cancer agent, andrographolide (AGP) in cancer cells, mouse xenograft tissues and patient derived organoids through gene/protein expression, gene silencing, and immunohistochemical analyses. Results: AGP treatment demonstrated significant expression of RASSF1A and PTEN TSGs in colon cancer and other cancer cells, mouse tissues and organoids. Depletion of RASSF1A with siRNA limited cyclin D1 and BAX expression. SiRNA depletion of PTEN, upstream regulator of RASSF1A resulted in a 50% reduction in RASSF1A expression. Histopathological analysis of the AGP treated tumor sections showed significant reduction in vessel size, microvascular density and tumor mitotic index suggesting suppression of angiogenesis. This was corroborated by protein analysis demonstrating significant reductions in angiogenesis signaling pathway molecules VEGF165, FOXM1, and pAkt, but significant elevation of the endogenous angiogenesis inhibitor Tsp-2. Treatment of cells with exogenous VEGF prevented the suppression of angiogenesis signaling by AGP, resulting in sustained expression of pAkt, an upstream down-regulator of RASSF1A. RASSF1A expression remained low in VEGF treated cells despite the addition of AGP. Conclusion: Our results demonstrate for the first time that AGP induces RASSF1A expression in colon cancer cells and is dependent on angiogenesis signaling events. Therefore, our research may facilitate novel therapeutic options for advanced colon cancer therapy. Copyright 2018 The Author(s). Published by S. Karger AG, Basel.
Identifier to cite or link to this itemhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85052473932&doi=10.1159%2f000492012&partnerID=40&md5=28570de8c91370b7e7c3d65e6f458e9b; http://hdl.handle.net/10713/9228
- Tandutinib inhibits the Akt/mTOR signaling pathway to inhibit colon cancer growth.
- Authors: Ponnurangam S, Standing D, Rangarajan P, Subramaniam D
- Issue date: 2013 May
- Lebein, a snake venom disintegrin, suppresses human colon cancer cells proliferation and tumor-induced angiogenesis through cell cycle arrest, apoptosis induction and inhibition of VEGF expression.
- Authors: Zakraoui O, Marcinkiewicz C, Aloui Z, Othman H, Grépin R, Haoues M, Essafi M, Srairi-Abid N, Gasmi A, Karoui H, Pagès G, Essafi-Benkhadir K
- Issue date: 2017 Jan
- Biglycan up-regulated vascular endothelial growth factor (VEGF) expression and promoted angiogenesis in colon cancer.
- Authors: Xing X, Gu X, Ma T, Ye H
- Issue date: 2015 Mar
- Increased reactive oxygen species levels cause ER stress and cytotoxicity in andrographolide treated colon cancer cells.
- Authors: Banerjee A, Banerjee V, Czinn S, Blanchard T
- Issue date: 2017 Apr 18
- Tunicamycin inhibits colon carcinoma growth and aggressiveness via modulation of the ERK-JNK-mediated AKT/mTOR signaling pathway.
- Authors: You S, Li W, Guan Y
- Issue date: 2018 Mar