TY - JOUR
T1 - Genetic inactivation of AKT1, AKT2, and PDPK1 in human colorectal cancer cells clarifies their roles in tumor growth regulation
AU - Ericson, Kajsa
AU - Gan, Christine
AU - Cheong, Ian
AU - Rago, Carlo
AU - Samuels, Yardena
AU - Velculescu, Victor E.
AU - Kinzler, Kenneth W.
AU - Huso, David L.
AU - Vogelstein, Bert
AU - Papadopoulos, Nickolas
PY - 2010/2/9
Y1 - 2010/2/9
N2 - Phosphotidylinositol-3-kinase (PI3K) signaling is altered in the majority of human cancers. To gain insight into the roles of members of this pathway in growth regulation, we inactivated AKT1, AKT2, or PDPK1 genes by targeted homologous recombination in human colon cancer cell lines. Knockout of either AKT1 or AKT2 had minimum effects on cell growth or downstream signaling. In contrast, knockout of both AKT1 and AKT2 resulted in markedly reduced proliferation in vitro when growth factors were limiting and severely affected experimental metastasis in mice. Unexpectedly, AKT1 and AKT2 appeared to regulate growth through FOXO proteins, but not through either GSK3β or mTOR. In contrast, inactivation of PDPK1 affected GSK3β and mTOR activation. These findings show that the PI3K signaling pathway is wired differently in human cancer cells than in other cell types or organisms, which has important implications for the design and testing of drugs that target this pathway.
AB - Phosphotidylinositol-3-kinase (PI3K) signaling is altered in the majority of human cancers. To gain insight into the roles of members of this pathway in growth regulation, we inactivated AKT1, AKT2, or PDPK1 genes by targeted homologous recombination in human colon cancer cell lines. Knockout of either AKT1 or AKT2 had minimum effects on cell growth or downstream signaling. In contrast, knockout of both AKT1 and AKT2 resulted in markedly reduced proliferation in vitro when growth factors were limiting and severely affected experimental metastasis in mice. Unexpectedly, AKT1 and AKT2 appeared to regulate growth through FOXO proteins, but not through either GSK3β or mTOR. In contrast, inactivation of PDPK1 affected GSK3β and mTOR activation. These findings show that the PI3K signaling pathway is wired differently in human cancer cells than in other cell types or organisms, which has important implications for the design and testing of drugs that target this pathway.
KW - Isogenic lines
KW - Metastasis
KW - Microenvironment
KW - PI3K
KW - PIK3CA
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UR - http://www.scopus.com/inward/citedby.url?scp=77249179196&partnerID=8YFLogxK
U2 - 10.1073/pnas.0914018107
DO - 10.1073/pnas.0914018107
M3 - Article
C2 - 20133737
AN - SCOPUS:77249179196
SN - 0027-8424
VL - 107
SP - 2598
EP - 2603
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 6
ER -