title: Akt phosphorylation associates with LOH of PTEN and leads to chemoresistance for gastric cancer.
abstract: Growth factor receptor-mediated signal transduction has been implicated in conferring resistance to conventional chemotherapy on cancer cells. We describe a pathway that involves AKT/PI3K to mediate chemoresistance in gastric cancer patients. Primary gastric carcinoma tissues and corresponding normal mucosa were obtained from 76 gastric cancer patients who underwent surgery in the Department of Surgery II in Kyushu University Hospital from the years 1996-2000. AKT activation was investigated by immunostaining with a phosphorylation-specific antibody, and LOH (loss of heterozygosity) of PTEN was studied in the same samples. AKT was phosphorylated in 22 cases (28.9%) of gastric cancer cases. AKT and phosphorylated AKT were not correlated with any clinicopathological factor. We found that the gastric cancer patients who had higher AKT phosphorylation (activated AKT) seemed to have LOH of PTEN (p = 0.0008). 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 (5-fluorouracil, adriamycin, mitomycin C and cis-platinum). The results of our 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 AKT may therefore be a novel molecular target for therapies or chemosensitivity tests that improve the outcomes of gastric cancer patients.
authors.affiliation: Department of Surgery and Science, Graduate School of Kyushu University, Fukuoka, Japan. okieiji@surg2.med.kyushu-u.ac.jp
authors.forename: Eiji
authors.initials: E
authors.lastname: Oki
authors.forename: Hideo
authors.initials: H
authors.lastname: Baba
authors.forename: Eriko
authors.initials: E
authors.lastname: Tokunaga
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Nakamura
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Ueda
authors.forename: Motonori
authors.initials: M
authors.lastname: Futatsugi
authors.forename: Kohjiro
authors.initials: K
authors.lastname: Mashino
authors.forename: Manabu
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Masahiko
authors.initials: M
authors.lastname: Ikebe
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kakeji
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Maehara
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D017931:DNA Primers; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007564:Japan; D019656:Loss of Heterozygosity; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics*; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D013274:Stomach Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000235:genetics* / Q000556:secondary; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D017931:DNA Primers; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human