Loss of PTEN function may account for reduced proliferation pathway sensitivity to LY294002 in human prostate and bladder cancer cells.
OBJECTIVE
Inhibition of phosphoinositide 3 (PI3)-kinase pathway is attractive for cancer treatment. To examine the role of the phosphatase and tensin homolog (PTEN) in the development of resistance to the treatment.


METHODS
We cultured human prostate cancer cells (DU145 and PC-3 cells) and bladder cancer cells (EJ-1 and UM-UC-3 cells) with a PI3-kinase inhibitor, LY294002 for more than 6 weeks and cell proliferation was studied. Activation of Akt1 and ERK was examined by immunoblotting. We introduced the wild type PTEN in UM-UC-3 cells and their proliferation along with the signaling pathways was also examined.


RESULTS
After 6 weeks, proliferation pathway sensitivity to LY294002 was reduced in cells expressing PTEN, but not in PTEN-null cells. PD98059, a MAPK/ERK kinase inhibitor, significantly inhibited proliferation of PTEN-expressing cells, but not PTEN-null cells. Stable PTEN expression in PTEN-null UM-UC-3 cells increased serum-induced ERK activation and sensitivity to PD98059-treatment, and reduced sensitivity to LY294002 after 6 weeks of exposure.


CONCLUSIONS
Loss of PTEN function may protect against resistance to PI3-kinase inhibitors through an addiction to the PI3-kinase/Akt pathway.
Kanda
Shigeru
S
Department of Molecular Microbiology and Immunology, Division of Endothelial Cell Biology, Nagasaki University Graduate School of Biomedical Science, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan. skanda-jua@umin.net
Kanetake
Hiroshi
H
Miyata
Yasuyoshi
Y
D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002867:Chromones / Q000627:therapeutic use*; D003001:Cloning, Molecular; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006801:Humans; D008081:Liposomes; D008297:Male; D008940:Mitotic Index; D009025:Morpholines / Q000627:therapeutic use*; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010957:Plasmids / Q000187:drug effects / Q000235:genetics; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics; D014162:Transfection; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000235:genetics*
D002867:Chromones; D004791:Enzyme Inhibitors; D008081:Liposomes; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D034741:RNA, Small Interfering; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human