Prognostic Significance of Activated Akt Expression in Pancreatic Ductal Adenocarcinoma

Abstract

Purpose: Akt is a serine/threonine kinase that plays a central role in tumorigenesis. Among the members of Akt family, Akt2 is associated with the development of human cancers. The present study was designed to clarify the prognostic significance of Akt2 and activated Akt expression in pancreatic ductal adenocarcinoma (PDAC). In addition, activated extracellular signal-regulated kinase 1 and 2 (ERK1/2) and the proliferation activity of tumor cells detected by Ki-67 immunohistochemistry were examined.Experimental Design: Immunohistochemical analysis was performed on paraffin-embedded specimens from 65 patients with PDAC; 36 males and 29 females with ages ranging from 48 to 79 years (median, 66 years) of age. Expression levels of Akt2, phosphorylated Akt (p-Akt), and phosphorylated ERK 1/2 (p-ERK 1/2) were categorized as either weaker (low intensity) or equal to stronger (high intensity) compared with those in the endothelial cells of the same specimens. For Ki-67 immunohistochemistry, cases were divided into two groups: level 1, Ki-67 labeling index (LI), <20%; level 2, Ki-67 LI, >20%.Results: Twenty-six (42.6%), 28 (45.9%), 39 (63.9%), and 46 (75.4%) of the tumors showed high intensity of Akt2, p-Akt, and p-ERK 1/2 expression, and Ki-67 LI level 2, respectively. A significant positive correlation was observed between Akt2 and p-Akt expression (P < 0.01). Multivariate analysis revealed that p-Akt expression, Ki-67 LI, and histological differentiation are independent prognosticators for PDAC.Conclusions: p-Akt expression is a significant prognostic indicator for PDAC. Inhibition of Akt is a possible molecular approach for treatment of PDAC.

In vitro synergistic cytotoxicity of gemcitabine and pemetrexed and pharmacogenetic evaluation of response to gemcitabine in bladder cancer patients

“…In particular, the reduction of phosphorylated Akt correlated with the enhancement of gemcitabine-induced apoptosis and antitumour activity, suggesting that the PI3K-Akt pathway plays a significant role in mediating drug resistance in several pancreatic cancer cells (Bondar et al, 2002). Moreover, an immunohistochemical analysis in patients who underwent curative resection revealed that p-Akt expression was a prognostic factor for overall survival in primary pancreatic adenocarcinoma (Yamamoto et al, 2004). Therefore, the inhibition of Akt might be a possible molecular target for novel therapeutic strategies and the present study demonstrated that pemetrexed significantly decreased the amount of the activated form of Akt.…”

Relation between outcomes and localisation of p-mTOR expression in gastric cancer

“…However, earlier studies of Akt expression in human cancers have yielded conflicting results. In pancreatic cancer, one study showed a correlation between higher p-Akt expression and shorter survival (Yamamoto et al, 2004), whereas another study showed the opposite (Chadha et al, 2006). Higher p-Akt expression was associated with poor outcomes in breast cancer (Zhou et al, 2004), and with lymph node metastasis or advanced disease stage in colorectal cancer (Itoh et al, 2002).…”

Select Biomarkers for Tumors of the Gastrointestinal Tract: Present and Future

“…Akt and its expression has been reported in pancreatic adenocarcinoma. Prognostic significance of activated Akt expression was reported in one study 153 that found that patients with low intensity p-Akt expression showed a significantly better 5-year survival rate than those with high expression, and univariate analysis revealed that p-Akt expression was significant in overall survival. Another study 154 found similar results, with expression of p-Akt correlating with survival both on univariate and multivariate analysis.…”