Colorectal cancer is the second leading cause of cancer-related deaths in the United States. Understanding the distinct genetic and epigenetic changes contributing to the establishment and growth of metastatic lesions is crucial for the development of novel therapeutic strategies. In a search for key regulators of colorectal cancer metastasis establishment, we have found that the serine/threonine kinase Akt2, a known proto-oncogene, is highly expressed in late-stage colorectal cancer and metastatic tumors. Suppression of Akt2 expression in highly metastatic colorectal carcinoma cells inhibits their ability to metastasize in an experimental liver metastasis model. Overexpression of wild-type Akt1 did not restore metastatic potential in cells with downregulated Akt2, thus suggesting non-redundant roles for the individual Akt isoforms. In contrast, Akt2 overexpression in wild-type PTEN expressing SW480 colorectal cancer cells led to the formation of micrometastases; however, loss of PTEN is required for sustained formation of overt metastasis. Finally, we found that the consequence of PTEN loss and Akt2 overexpression function synergistically to promote metastasis. These results support a role for Akt2 overexpression in metastatic colorectal cancer and establish a mechanistic link between Akt2 overexpression and PTEN mutation in metastatic tumor establishment and growth. Taken together, these data suggest that Akt family members have distinct functional roles in tumor progression and that selective targeting of the PI3K/Akt2 pathway may provide a novel treatment strategy for colorectal cancer metastasis.

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