Cancer Biology

Tumors Akt Through ARK

Science's STKE  13 Apr 2004:
Vol. 2004, Issue 228, pp. TW132
DOI: 10.1126/stke.2282004TW132


The invasive activity of tumor cells underlies the spread of cancer. Tumor cells must detach, migrate, and penetrate target sites where they continue to proliferate. Various invasive cancers are associated with increased activity of Akt, a serine-threonine kinase. Although many Akt substrates have been identified, the specific downstream effectors of invasive tumor cell behavior have not been defined. Suzuki et al. report that the target substrate ARK5, a catalytic subunit of adenosine 5´-monophosphate (AMP)-activated protein kinase (AMPK) is essential to Akt involvement in tumor metastasis. Overexpression of ARK5 in human pancreatic or colon cancer cell lines increased their invasive activity, an effect dependent on active Akt. Suppression of ARK5 function by either RNA interference or expression of a dominant-negative form of ARK5 eliminated the effect on invasive activity. ARK5 also stimulated production of matrix type 1 matrix metalloproteinase (MT1-MMP), an activator of MMPs that facilitate metastasis. Transplantation of tumor cells overexpressing ARK5 into nude mice accelerated tumorigenesis and metastasis. Cells from these tumors contained abundant phosphorylated Akt (a modification usually associated with activation of the kinase) and showed reduced necrotic cell death. Interestingly, these tumors thrived in the absence of increased angiogenesis. Because AMPKs can promote tumor cell survival during stressful conditions such as low oxygen and nutrient starvation, the authors propose that activation of ARK5 through Akt may allow tumor cells to thrive in the absence of increased microvasculature, and up-regulate the MMP activity that promotes metastasis.

A. Suzuki, J. Lu, G. Kusakai, A. Kishimoto, T. Ogura, H. Esumi, ARK5 is a tumor invasion-associated factor downstream of Akt signaling. Mol. Cell Biol. 24, 3526-3535 (2004). [Abstract] [Full Text]