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 5 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. ' 2005 Wiley-Liss, Inc.

RUNX3-mediated transcriptional inhibition of Akt suppresses tumorigenesis of human gastric cancer cells

“…Thus, we concluded that Akt1 overexpression in gastric cancer might associate with loss of RUNX3 and suggested a novel mechanism that RUNX3 participated in cell proliferation inhibition as a role of tumor suppressor ( Figure 7). Overactivation of Akt in cancer cells is often regarded as the results of chromosome deletion, genetic mutation and gene amplification of the molecules that can regulate the activity of Akt, like PTEN deletion (Oki et al, 2005) and PIK3CA (PI3K) gene mutation . However, the genetic alternation of Akt itself is relatively low incidence in gastric cancer (Soung et al, 2006).…”

Akt associates with nuclear factor κB and plays an important role in chemoresistance of gastric cancer cells

“…Akt was characterized initially as the human homologue of the viral oncogene v-Akt from the transforming retrovirus Akt8 (22). Three isoforms of Akt have been identified, the Akt1, Akt2 and Akt3, all of which share a high degree of homology at the amino acid level (23,24).…”

“…For example, Akt phosphorylates the pro-apoptotic Bcl-2 partner Bad (22), which binds to and blocks the activity of Bcl-x, a cell survival factor. Akt can also inactivate initiation caspase-9 and repress the Forkhead transcription factor FKHRL-1, which regulates the apoptosis-inducing Fas ligand expression (33).…”

Roles of PTEN (Phosphatase and Tensin Homolog) in Gastric Cancer Development and Progression

“…Some studies have shown that the LOH status of PTEN can impact sensitivity to chemotherapy and hence, the prognosis in patients with gastric cancer. Hence, it may also be used as an independent prognostic tool (Oki et al, 2005;Oki et al, 2006;Chong et al, 2013).…”