Tumor suppressor ARF inhibits HER-2/neu-mediated oncogenic growth.
HER2/neu, a receptor tyrosine kinase oncogene, promotes mitogenic growth and antiapoptotic activity in cancer cells. Strong expression of HER2/neu in cancers has been associated with poor prognosis. Alternative reading frame protein (ARF), a tumor suppressor protein encoded by a gene located in the Ink4a/ARF gene locus, is frequently inactivated in human cancers. Little is known about the tumor suppressor role of ARF in HER2/neu-overexpressing cancers. Here, we applied the ARF gene as a tumor-suppressive agent for HER2/neu-overexpressing cells under the control of a tetracycline (tet)-regulated gene expression system. We found that ARF antagonized protein kinase B (PKB)/Akt-mediated p27Kip1 phosphorylation and increased p27 stability in HER2/neu-overexpressing cells. ARF expression also led to decreased levels of Cul1 and Skp2, two proteins involved in p27 degradation. We also found that ARF caused apoptosis in HER2/neu-overexpressing cells, and sensitized cells to apoptosis induced by the chemotherapeutic agents taxol and 2-methoxyestradiol. Most significantly for clinical application, we found that ARF inhibited HER2/neu-mediated cell growth, transformation, and tumorigenesis. These findings indicate that modulation of ARF activity may be a useful therapeutic intervention in HER2-overexpressing cancers.
Zhang
Yujiang
Y
Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Yang
Heng-Yin
HY
Zhang
Xiao-Chun
XC
Yang
Huiling
H
Tsai
Mayli
M
Lee
Mong-Hong
MH
D016475:3T3 Cells; D000818:Animals; D001483:Base Sequence; D002455:Cell Division / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D017931:DNA Primers; D017930:Genes, Reporter; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D008822:Mice, Transgenic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000172:deficiency / Q000235:genetics*; D014162:Transfection; D014183:Transplantation, Heterologous
D017931:DNA Primers; D018719:Erb-b2 Receptor Tyrosine Kinases