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

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-rasgene. 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 Ras 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-ras 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.

PIN1 Maintains Redox Balance via the c-Myc/NRF2 Axis to Counteract Kras-Induced Mitochondrial Respiratory Injury in Pancreatic Cancer Cells

“…Constitutive activation of Kras drives uncontrolled proliferation and enhances the survival of cancer cells, primarily through the Ras-Raf-MEK-ERK and PI3K-Akt-mTOR pathways (26)(27)(28)(29)(30)(31)(32)(33). In the past few decades, extensive efforts have been focused on identifying effective molecular targets for this oncogene (34). However, these efforts have failed, and Kras is still considered to be an undruggable target.…”

HTBPI, an active phenanthroindolizidine alkaloid, inhibits liver tumorigenesis by targeting Akt

“…Recent deep molecular profiling efforts have identified several dysregulated signaling pathways in HCC including Wnt/β‐catenin, Ras/Raf/MEK/ERK, and PI3K/Akt/mTOR axis 8,9 . Interestingly, autophagy, a “self‐eating” process that clears intracellular waste, plays an important role in the development of tumors, either inhibiting or accelerating tumor formation, depending on the state of tumor formation 10,11 .…”

A genetic variant in PIK3R1 is associated with pancreatic cancer survival in the Chinese population

“…It is well recognized that the PI3K‐AKT signaling plays critical roles in metastasis of cancers including PC . It promotes cellular events such as invasion, migration and epithelial‐mesenchymal transition via regulation of different transcription factors . PIK3R1 , which encodes the 85 kD regulatory subunit of PI3K, functions primarily as a regulator of the p110α catalytic product.…”

“…[27][28][29][30] It promotes cellular events such as invasion, migration and epithelial-mesenchymal transition via regulation of different transcription factors. [31][32][33] PIK3R1, which encodes the 85 kD regulatory subunit of PI3K, functions primarily as a regulator of the p110α catalytic product. Its mutations and abnormal expression were reported to impair PI3K function, and further cause disease.…”