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

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          Abstract

          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.

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          Author and article information

          Journal
          Cancer Lett.
          Cancer letters
          Elsevier BV
          1872-7980
          0304-3835
          December 01 2017
          : 410
          Affiliations
          [1 ] Division of Molecular Biology, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, 650-0017, Japan.
          [2 ] Drug Discovery Science, Division of Advanced Medical Science, Department of Science, Technology and Innovation, Kobe University Graduate School of Science, Technology and Innovation, Kobe, 650-0017, Japan. Electronic address: sfumi@med.kobe-u.ac.jp.
          [3 ] Division of Molecular Biology, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, 650-0017, Japan. Electronic address: kataoka@people.kobe-u.ac.jp.
          Article
          S0304-3835(17)30567-0
          10.1016/j.canlet.2017.09.017
          28951129
          9a4c2124-5975-46a2-8127-a7e63ed41680
          History

          PI3K,Ras,Ras inhibitors,LOX,Metastasis,HIF-1α
          PI3K, Ras, Ras inhibitors, LOX, Metastasis, HIF-1α

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