Akt-mediated YB-1 phosphorylation induces resistance for chemotherapy of gastric cancer

Abstract

4554 Background: Y-box-binding protein 1 (YB-1), a member of the DNA-binding protein family which contains a cold-shock domain, has pleiotropic functions in response to stimuli of the AKT/PI3K signal pathway. We have previously described a pathway that involves PTEN/AKT/PI3K, thereby mediating chemoresistance in gastric cancer patients. We studied the Akt-mediated YB-1 phosphorylation and resistance to anti-cancer drugs for the treatment of gastric cancer. Methods: Primary gastric carcinoma tissue and the corresponding normal mucosa were both obtained from 81 gastric cancer patients who underwent surgery in the Department of Surgery II at Kyushu University Hospital from the years 1996 to 2000. YB-1 nuclear expression was investigated by immunostaining while AKT activation was investigated by immunostaining with a phosphorylation-specific antibody. The chemotherapeutic sensibilities of these patients were investigated using an MTT assay. LOH of PTEN was studied using a DNA sequencer with D10S796 and D10S1173 microsatellite markers in the same samples. Results: We found the activated AKT to be associated with an increased resistance to multiple chemotherapeutic agents, including those currently used on gastric cancer patients (5-fluorouracil, adriamycin, mitomycin C, and cis-platinum). The YB-1 nuclear expression was recognized in some patients and they closely correlated with a high expression of phosphorylated AKT. A high level of AKT phosphorylation (activated AKT) correlated closely with the LOH of PTEN (p < 0.0008), and the prognosis of patients who had LOH of PTEN was significantly poor in comparison to the other patients. Conclusions: The results of this study indicate that AKT activation and LOH of PTEN mediated the YB-1 activation, thus suggesting that they play an important role in conferring broad-spectrum chemoresistance in gastric cancer patients. These findings thus support the carrying out of new clinical trials for investigations of combination chemotherapy using conventional drugs with a new generation of signal transduction inhibitors. No significant financial relationships to disclose.