Impact Of Pten/Akt/Pi3k Signal Pathway On The Chemotherapy For Gastric Cancer.

4034 Background: Growth factor receptor-mediated signal transduction has been recently implicated in conferring resistance to conventional chemotherapy on cancer cells. We have described a pathway that involves AKT/PI3K to mediate chemoresistance in gastric cancer patients. The phosphatase activity of PTEN is crucial in controlling the phosphatidylinositol-3 (PI-3) kinase signal transduction pathway and in the activation of the protein kinase B(PKB/Akt) proto-oncogene. This indicates that PTEN exerts its tumor-suppressor function by negatively regulating the anitapoptotic PI3-kinase/AKT signaling pathway. Methods: Primary gastric carcinoma tissues and corresponding normal mucosa were obtained from 119 gastric cancer patients who underwent surgery in the Department of Surgery II in Kyushu University Hospital from the years 1996 to 2000. Methylation of PTEN was studied with methylation-specific PCR and LOH (loss of heterozygosity) of PTEN was studied using a DNA sequencer with D10S796 and D10S1173 microsatellite marker in the same samples. AKT activation was investigated by immunostaining with a phosphorylation-specific antibody. The chemotherapeutic sensibilities of these patients were investigated using an MTT assay. Results: We found that methylation of PTEN was rarely recognized, However, the gastric cancer patients who had a higher AKT phosphorylation (activated AKT) appeared to have LOH of PTEN (p < 0.0008), and the prognosis of the patient who has LOH of PTEN was significantly poor. When the chemotherapeutic sensibilities of these patients were studied in an MTT assay, it was found that the activated AKT was associated with increased resistance to multiple chemotherapeutic agents, which included those currently used on gastric cancer patients (5-fluorouracil, adriamycin, mitomycin C, and cis-platinum). Conclusions: The results of this study indicate that AKT activation and LOH of PTEN plays an important role in conferring a broad-spectrum chemoresistance in gastric cancer patients. It also indicates that clinical trials for an appropriate chemotherapy combination with conventional drugs and a new generation of signal transduction inhibitors that inhibit the PTEN/AKT pathway should be considered in treating gastric cancer in the near future. No significant financial relationships to disclose.