Differential sensitivity of human endometrial carcinoma cells with different PTEN expression to mitogen-activated protein kinase signaling inhibits and implications for therapy.
OBJECTIVE
Prior studies in different tumor models have shown that, under conditions of PTEN deficiency, the mitogen-activated protein kinase (MAPK) signaling pathway appear to play a major role in the tumor cell's proliferative and survival pathway, and that pharmacological inhibition of this pathway results in tumor growth inhibition. This study aimed to explore whether sensitivity to p38MAPK inhibitors are specifically due to status of PTEN in endometrial cancer cells.


METHODS
We developed a series of endometrial cancer cell lines with different PTEN expressions (Ishikawa, RL-952, HEC-1B and HEC-1A cells) or introduced the wild-type PTEN and PTEN-siRNA in four endometrial cancer cells to change its PTEN expression with a p38MAPK inhibitor, SB203580 for 2 days. Cell proliferation, cell apoptosis, and cell cycle distribution were studied, and activation of AKT, ATF-2, and p38MAPK was examined by Western blotting.


RESULTS
In cultivated PTEN-deficient endometrial cancer cells, in addition to an activation of AKT, a phosphorylation of p38MAPK and ATF-2 was evident, while PTEN-positive endometrial cancer cells lacked AKT activation but revealed a reduced expression of p-p38MAPK and p-ATF-2. These PTEN-deficient endometrial cancer cells demonstrated an increased sensitivity to the anti-proliferative effects induced by SB203580 compared with the PTEN-positive endometrial cancer cells, which corresponded to alterations in cell cycle response and cell apoptosis.


CONCLUSIONS
PTEN-deficient endometrial cancer cells exhibit higher p38MAPK activity, and genetic studies demonstrate that p38MAPK functions dependently of AKT. Furthermore, PTEN loss sensitizes cells to p38MAPK inhibition in endometrial carcinoma cells. These findings indicate that inhibitors of p38MAPK have the potential to be effective in the treatment of endometrial cancer patients with PTEN-deficient tumors and should be evaluated in this setting.
Xiao
Lan
L
Department of Obstetrics and Gynecology, The Third Affiliated Hospital, Sun Yat-sen University, 600 TianHe Road, 510630 Guangzhou, People's Republic of China.
Yang
Yue-bo
YB
Li
Xiao-mao
XM
Xu
Cheng-fang
CF
Li
Tian
T
Wang
Xiao-yun
XY
D051698:Activating Transcription Factor 2 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D012680:Sensitivity and Specificity; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; D007093:Imidazoles; D011725:Pyridines; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C093642:SB 203580