The inhibition of Akt-Pdpk1 interaction efficiently suppresses the growth of murine primary liver tumor cells.
The lack of primary liver tumor cells has hampered testing of potential chemotherapeutic agents in vitro. To overcome this issue we developed a primary mouse liver tumor cell line K07074. The K07074 cells were immortal, exhibited a biliary phenotype, formed colonies in soft agar and displayed an increase in Hedgehog, Notch and Akt signaling. To study the effect of single and combined inhibition of the liver tumor-related pathways on the growth of K07074 cells we treated these with small-molecule antitumor agents. While the inhibition of Akt and Notch pathways strongly inhibited the growth of K07074 cells the inhibition of Wnt and Hedgehog pathways was less efficient in cell growth suppression. Interestingly, the inhibition of Akt pathway at the level of Akt-Pdpk1 interaction was sufficient to suppress the growth of tumor cells and no significant additive effect could be detected when co-treated with the inhibitors of Wnt, Hedgehog or Notch pathways. Only when suboptimal doses of Akt-Pdpk1 interaction inhibitor NSC156529 were used an additive effect with Notch inhibition was seen. We conclude that the Akt pathway inhibitor NSC156529 is potentially useful as single treatment for liver tumors with hyperactivated Akt signaling.
Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
Kristina
K
Mäemets-Allas
Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
Denis
D
Belitškin
Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia; Karolinska Institutet, Stockholm, Sweden. Electronic address: viljar.jaks@ut.ee.
Viljar
V
Jaks
D064413:3-Phosphoinositide-Dependent Protein Kinases / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D016147:Genes, Tumor Suppressor / Q000187:drug effects; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D064413:3-Phosphoinositide-Dependent Protein Kinases; C578564:Pdpk1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt
AKT inhibitor; Cancer treatment; Cell signaling; PDPK1; Protein kinase B