A novel member of the human AMPK family, ARK5, was recently discovered to be a key molecule in mediating cancer cell migration activity in human pancreas cancer cell line PANC-1, and its activation was found to be induced by Akt-dependent phosphorylation at Ser 600. DNA array analysis with 241 paired cDNAs from 13 different types of tumors and corresponding normal tissues derived from cancer patients revealed ARK5 overexpression in the samples of colorectal cancer. ARK5 expression was measured and an in vitro invasion assay was performed in six human colorectal cancer cell lines, WiDr, HCT-15, DLD-1, SW620, LoVo, and SW480, and since high invasion activity was concordant with higher ARK5 expression, ARK5 expression was examined in relation to tumor progression and metastatic activity in clinical samples. In 56 clinical samples of primary colorectal cancers and their liver metastases, higher ARK5 expression was observed in the samples from more advanced cases, and much higher expression was observed in the liver metastases. In situ hybridization analysis showed ARK5 overexpression in tumor cells. Based on these findings, we propose that ARK5 overexpression is involved in tumor progression of colon cancer clinically. Because of excessive proliferation, energy demands, and insufficient and structurally and functionally inappropriate angiogenesis, tumor tissues are often exposed to an insufficient blood supply, and in turn are usually exposed to both hypoxia and nutrient starvation in their microenvironment.1 The impact of the microenvironment on the progression of various tumors has been clearly recognized. The importance of the response of tumor cells to hypoxic conditions has long been studied, 2-4 and the angiogenic ability of tumors was first recognized as a key factor in tumor biology about 30 years ago by Folkman. 5 The molecular mechanism of tumor angiogenesis, and its control mechanisms have been thoroughly studied. 6,7 Excessive tumor angiogenesis is often naively regarded as improving tumor's blood supply, but tumor hypoxia is now known to be a good marker for poor prognosis in various cancers. 8 -10 When cells and tissues are exposed to hypoxia, they sustain their excessive growth and proliferation in this adverse environment by improving blood flow, cell cycle regulation, and energy metabolism.11,12 These reactions are called the hypoxic response, and hypoxia-inducible factor 1 (HIF-1) is known to be a key transcriptional factor in the response. HIF-1 transactivates a series of hypoxia response genes, including the genes encoding VEGF, erythropoietin, and glycolytic enzymes, in response to hypoxia, and for this reason the ability of tumor cells to produce angiogenic factors is often correlated with tumor's ability to invade, metastasize, and progress.
13-15Based on these observations, it has been proposed that exposure to hypoxia might stimulate the ability of tumor cells to produce angiogenic factors and in turn tumor stimulate invasion and metastasis by the tumor 16 -18 and that under these condit...