Akt blocks breast cancer cell motility and invasion through the transcription factor NFAT.
The phosphoinositide 3-kinase (PI 3-K) signaling axis is intimately associated with deregulated cancer cell growth, primarily by promoting increased survival through Akt/PKB (protein kinase B). However, there is relatively little information on the role of Akt in cancer cell motility, a key phenotype of invasive carcinomas. Here we report that activation of Akt inhibits carcinoma migration and invasion of breast cancer cells. Conversely, downregulation of Akt using RNA interference increased migration and invasion. Akt blunts invasion by inhibiting the transcriptional activity of NFAT (nuclear factor of activated T cells). Specifically, signaling through Akt reduces NFAT expression levels due to ubiquitination and proteasomal degradation, mediated by the E3 ubiquitin ligase HDM2. These results indicate that while Akt can promote tumor progression through increased cell survival mechanisms, it can block breast cancer cell motility and invasion by a mechanism that depends, at least in part, on the NFAT transcription factor.
Yoeli-Lerner
Merav
M
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
Yiu
Gary K
GK
Rabinovitz
Isaac
I
Erhardt
Peter
P
Jauliac
Sebastien
S
Toker
Alex
A
D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D002464:Cell Migration Inhibition; D002465:Cell Movement / Q000502:physiology*; D005260:Female; D006801:Humans; D051379:Mice; D050778:NFATC Transcription Factors / Q000502:physiology*; D041681:NIH 3T3 Cells; D009361:Neoplasm Invasiveness; D046988:Proteasome Endopeptidase Complex / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000502:physiology; D025801:Ubiquitin / Q000378:metabolism
D050778:NFATC Transcription Factors; D025801:Ubiquitin; D051736:Proto-Oncogene Proteins c-mdm2; D051057:Proto-Oncogene Proteins c-akt; D046988:Proteasome Endopeptidase Complex