Akt2 overexpression plays a critical role in the establishment of colorectal cancer metastasis

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.

[1]  D. Wong,et al.  Dissecting the Akt/Mammalian Target of Rapamycin Signaling Network: Emerging Results from the Head and Neck Cancer Tissue Array Initiative , 2007, Clinical Cancer Research.

[2]  Carlo Rago,et al.  Mutant PIK3CA promotes cell growth and invasion of human cancer cells. , 2005, Cancer cell.

[3]  B. Karlan,et al.  Overexpression of AKT2/protein kinase Bbeta leads to up-regulation of beta1 integrins, increased invasion, and metastasis of human breast and ovarian cancer cells. , 2003, Cancer research.

[4]  I. Macdonald,et al.  Activated ras regulates the proliferation/apoptosis balance and early survival of developing micrometastases. , 2002, Cancer research.

[5]  H. Shimada,et al.  Whole-body optical imaging of green fluorescent protein-expressing tumors and metastases. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[6]  J. Testa,et al.  Frequent activation of AKT2 kinase in human pancreatic carcinomas , 2002, Journal of cellular biochemistry.

[7]  R. Vessella,et al.  Increased AKT Activity Contributes to Prostate Cancer Progression by Dramatically Accelerating Prostate Tumor Growth and Diminishing p27Kip1 Expression* , 2000, The Journal of Biological Chemistry.

[8]  M. Hara,et al.  A mouse model for studying intrahepatic islet transplantation. , 2004, Transplantation.

[9]  G. Mills,et al.  A new mutational AKTivation in the PI3K pathway. , 2007, Cancer cell.

[10]  N. Dubrawsky Cancer statistics , 1989, CA: a cancer journal for clinicians.

[11]  Domenico Coppola,et al.  Frequent activation of AKT2 and induction of apoptosis by inhibition of phosphoinositide-3-OH kinase/Akt pathway in human ovarian cancer , 2000, Oncogene.

[12]  C. Sawyers,et al.  The phosphatidylinositol 3-Kinase–AKT pathway in human cancer , 2002, Nature Reviews Cancer.

[13]  S Bengmark,et al.  The natural history of primary and secondary malignant tumors of the liver I. The prognosis for patients with hepatic metastases from colonic and rectal carcinoma by laparotomy , 1969, Cancer.

[14]  P. Cohen,et al.  Role of Translocation in the Activation and Function of Protein Kinase B* , 1997, The Journal of Biological Chemistry.

[15]  Lewis C Cantley,et al.  The phosphoinositide 3-kinase pathway. , 2002, Science.

[16]  I. Fidler,et al.  In vivo selection of highly metastatic cells from surgical specimens of different primary human colon carcinomas implanted into nude mice. , 1988, Cancer research.

[17]  A. Jemal,et al.  Cancer Statistics, 2008 , 2008, CA: a cancer journal for clinicians.

[18]  Robert A Copeland,et al.  Characterization of an Akt kinase inhibitor with potent pharmacodynamic and antitumor activity. , 2008, Cancer research.

[19]  Shuang-yin Han,et al.  Akt1/protein Kinase Bα is Involved in Gastric Cancer Progression and Cell Proliferation , 2008, Digestive Diseases and Sciences.

[20]  R. Parsons,et al.  PTEN: life as a tumor suppressor. , 2001, Experimental cell research.

[21]  Alfonso Bellacosa,et al.  AKT plays a central role in tumorigenesis , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[22]  J. Cheng,et al.  Molecular alterations of the AKT2 oncogene in ovarian and breast carcinomas , 1995, International journal of cancer.

[23]  Yiling Lu,et al.  Exploiting the PI3K/AKT Pathway for Cancer Drug Discovery , 2005, Nature Reviews Drug Discovery.

[24]  E. Holland,et al.  Perifosine inhibits multiple signaling pathways in glial progenitors and cooperates with temozolomide to arrest cell proliferation in gliomas in vivo. , 2005, Cancer research.

[25]  B. Evers,et al.  Targeted Molecular Therapy of the PI3K Pathway: Therapeutic Significance of PI3K Subunit Targeting in Colorectal Carcinoma , 2006, Annals of surgery.