Ras inhibitors display an anti-metastatic effect by downregulation of lysyl oxidase through inhibition of the Ras-PI3K-Akt-HIF-1α pathway

• Published in: Cancer letters 2017-12, Vol.410, p.82-91
• Main Authors: Yoshikawa, Yoko, Takano, Osamu, Kato, Ichiro, Takahashi, Yoshihisa, Shima, Fumi, Kataoka, Tohru
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Animals; Antineoplastic Agents - pharmacology; Cancer; Cell culture; Cell Movement - drug effects; Cell proliferation; Colorectal carcinoma; Dose-Response Relationship, Drug; Down-Regulation; Enzyme Inhibitors - pharmacology; Extracellular matrix; Female; Gene expression; Gene Expression Regulation, Neoplastic; HIF-1α; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Hypoxia-inducible factors; Immunoglobulins; Inhibition; Inhibitor drugs; Inhibitors; Kinases; Liquid oxygen; LOX; Lung Neoplasms - enzymology; Lung Neoplasms - genetics; Lung Neoplasms - prevention & control; Lung Neoplasms - secondary; Lungs; Lysyl oxidase; MCF-7 Cells; Metastases; Metastasis; Mice; Mice, Nude; Mutation; Neoplasm Invasiveness; NIH 3T3 Cells; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - enzymology; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - pathology; Phosphatidylinositol 3-Kinase - metabolism; Phosphorylation; PI3K; Protein-Lysine 6-Oxidase - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Proto-Oncogene Proteins p21(ras) - antagonists & inhibitors; Proto-Oncogene Proteins p21(ras) - genetics; Proto-Oncogene Proteins p21(ras) - metabolism; Ras; Ras inhibitors; RNA Interference; Rodents; Signal Transduction - drug effects; siRNA; Transfection; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2017.09.017

Metastasis stands as the major obstacle for the survival from cancers. Nonetheless most existing anti-cancer drugs inhibit only cell proliferation, and discovery of agents having both anti-proliferative and anti-metastatic properties would be more beneficial. We previously reported the discovery of small-molecule Ras inhibitors, represented by Kobe0065, that displayed anti-proliferative activity on xenografts of human colorectal cancer (CRC) cell line SW480 carrying the K-rasG12Vgene. Here we show that treatment of cancer cells carrying the activated ras genes with Kobe0065 or a siRNA targeting Ras downregulates the expression of lysyl oxidase (LOX), which has been implicated in metastasis. LOX expression is enhanced by co-expression of RasG12V through activation of phosphatidylinositol 3-kinase (PI3K)/Akt and concomitant accumulation of hypoxia-inducible factor (HIF)-1α. Furthermore, Kobe0065 effectively inhibits not only migration and invasion of cancer cells carrying the activated ras genes but also lung metastasis of human CRC cell line SW620 carrying the K-rasG12V gene. Collectively, these results indicate that Kobe0065 prevents metastasis through inhibition of the Ras-PI3K-Akt-HIF-1α-LOX signaling and suggest that Ras inhibitors in general might exhibit both anti-proliferative and anti-metastatic properties toward cancer cells carrying the activated ras genes. •Ras activation upregulates the expression of lysyl oxidase (LOX) through PI3K/Akt-mediated HIF-1α accumulation.•Treatment with a Ras inhibitor or a siRNA targeting Ras reduces LOX expression in cancer cells carrying the activated ras.•A Ras inhibitor abrogates migration, invasion and lung metastasis of cancer cells carrying the activated ras.•Ras inhibitors show both anti-proliferative and anti-metastatic properties toward cancer cells carrying the activated ras.