Downregulation of Akt1 inhibits anchorage-independent cell growth and induces apoptosis in cancer cells.
The serine/threonine kinases, Akt1/PKBalpha, Akt2/PKBbeta, and Akt3/PKBgamma, play a critical role in preventing cancer cells from undergoing apoptosis. However, the function of individual Akt isoforms in the tumorigenicity of cancer cells is still not well defined. In the current study, we used an Akt1 antisense oligonucleotide (AS) to specifically downregulate Akt1 protein in both cancer and normal cells. Our data indicate that Akt1 AS treatment inhibits the ability of MiaPaCa-2, H460, HCT-15, and HT1080 cells to grow in soft agar. The treatment also induces apoptosis in these cancer cells as demonstrated by FACS analysis and a caspase activity assay. Conversely, Akt1 AS treatment has little effect on the cell growth and survival of normal human cells including normal human fibroblast (NHF), fibroblast from muscle (FBM), and mammary gland epithelial 184B5 cells. In addition, Akt1 AS specifically sensitizes cancer cells to typical chemotherapeutic agents. Thus, Akt1 is indispensable for maintaining the tumorigenicity of cancer cells. Inhibition of Akt1 may provide a powerful sensitization agent for chemotherapy specifically in cancer cells.
Liu
X
X
Cancer Research, Pharmaceutical Product Division, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA. xuesong.liu@ln.ssw.abbott.com
Shi
Y
Y
Han
E K
EK
Chen
Z
Z
Rosenberg
S H
SH
Giranda
V L
VL
Luo
Y
Y
Ng
S C
SC
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003114:Colony-Forming Units Assay; D004396:Coloring Agents; D003574:Cytochrome c Group / Q000378:metabolism; D015536:Down-Regulation; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010078:Oxazines; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D014407:Tumor Cells, Cultured / Q000378:metabolism / Q000473:pathology*; D014966:Xanthenes
D000970:Antineoplastic Agents; D004396:Coloring Agents; D003574:Cytochrome c Group; D016376:Oligonucleotides, Antisense; D010078:Oxazines; D011518:Proto-Oncogene Proteins; D014966:Xanthenes; C005843:resazurin; D011065:Poly(ADP-ribose) Polymerases; C494918:AKT1 protein, human; C494921:AKT2 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases