Search

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-ras(G12V) gene. 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(G12V) 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(G12V) gene. Collectively, these results indicate that Kobe0065 prevents metastasis through inhibition of the Ras-P13K-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.

Book

The stratigraphic distribution and abundance of molluscs and planktonic foraminifera within a sixth-order (41 kyr) depositional sequence of the early Pleistocene Omma Formation in central Japan provide several important information on the Sea of Japan since 2.5 Ma. The sea possibly experienced three substages in the paleoceanographic history since then. During substage I (2.5–1.71 Ma, oxygen isotope stage 60/59), cold northern surface water prevailed due to the closure of the sea's southern entrance. During substage II (1.71–1.52 Ma, stage 51), the warm Tsushima Current flowed into the sea from the south during interglacial highstands. During substage III (1.52–0 Ma), isolation of the Sea of Japan was reinforced by narrowing and/or shallowing of the northern entrance. These changes were caused by some local tectonic movements that affected topography of the southern and northern straits. Inflow of the Tsushima Current resulted in migration of warm-water organisms into the Sea of Japan during interglacial stages, and acted as a barrier to the migration of terrestrial organisms between East Asia and Japanese Islands.