Incidence, mechanism and prognostic value of activated AKT in pancreas cancer

Abstract

When activated, the serine/threonine kinase AKT mediates an antiapoptotic signal implicated in chemoresistance of various cancers. The mechanism(s) of AKT activation are unknown, though overexpression of HER-2/neu has been implicated in breast cancer. Therefore, we determined the incidence of activated AKT in human pancreatic cancer, whether HER-2/neu is involved in AKT activation, and if AKT activation is associated with biologic behaviour. HER-2/neu expression and AKT activation were examined in seven pancreatic cancer cell lines by Western blotting. The in vitro effect of HER-2/neu inhibition on AKT activation was similarly determined. Finally, 78 pancreatic cancer specimens were examined for AKT activation and HER-2/neu overexpression, and correlated with the clinical prognostic variable of histologic grade. HER-2/neu was overexpressed in two of seven cell lines; these two cell lines demonstrated the highest level of AKT activation. Inhibition of HER-2/neu reduced AKT activation in vitro. AKT was activated in 46 out of 78 (59%) of the pancreatic cancers; HER-2/neu overexpression correlated with AKT activation (P ¼ 0.015). Furthermore, AKT activation was correlated with higher histologic tumour grade (P ¼ 0.047). Thus, it is concluded that AKT is frequently activated in pancreatic cancer; this antiapoptotic signal may be mediated by HER-2/neu overexpression. AKT activation is associated with tumour grade, an important prognostic factor.

Retracted: In vitro and in vivo molecular evidence of genistein action in augmenting the efficacy of cisplatin in pancreatic cancer

“…In addition, Akt activation due to phosphorylation of Akt protein at Thr308 or Ser473 also augments cellular resistance to various treatments. [9][10][11] Based on the notion that inhibition of constitutively active Akt and NF-jB signaling may attenuate chemo-resistance, hence strategies specifically targeting the inhibition of NF-jB and Akt have emerged as an alternative and attractive therapeutic arsenal for cancer treatment. [12][13][14][15] In recent years, naturally occurring compounds in the diet have gained considerable attention because of their alleged beneficial effects as chemopreventive agents, partly attributable to dual inactivation of NF-jB and Akt signaling cascade.…”

Effect of Rapamycin Alone and in Combination with Antiangiogenesis Therapy in an Orthotopic Model of Human Pancreatic Cancer

“…Nave et al (13) found that Akt/protein kinase B regulates the phosphorylation state of mTOR directly. Akt, an apoptotic regulator, is frequently activated in pancreatic cancer (14). Although rapamycin is not considered to be an antiapoptotic factor, a recent publication established Akt signaling through mTOR and eIF-4E as an important mechanism of oncogenesis and drug resistance in vivo by proving that rapamycin can restore apoptotic sensitivity to lymphomas expressing Akt in vivo (15).…”

MicroRNA expression alterations are linked to tumorigenesis and non-neoplastic processes in pancreatic ductal adenocarcinoma

“…The importance of miR-146 is further underscored by its upregulation evidenced in a number of epithelial tumors . Interestingly, activated NF-kB signalling has been demonstrated in PDAC and is likely the result of an activated phosphatidylinositol 3-OH kinase (PI3K)/AKT signalling pathway (Altomare et al, 2003;Schlieman et al, 2003). It will be important to identify and test miR-146 downstream target genes, such as NUMB, SP8 or KLF7 (Supplementary Table 6), to gain insights into the signalling pathways altered by the aberrant expression of this miRNA.…”