Increased expression of pAKT is associated with radiation resistance in cervical cancer

Abstract

Phosphorylated AKT (pAKT) is a major contributor to radioresistance in human cancers. The aim of this study was to investigate the association of pAKT expression and radiation resistance in cervical cancer. A retrospective review was made of the records of 27 women who received primary radiation therapy due to locally advanced cervical cancer (LACC) with FIGO stage IIB -IVA. Nine patients regarded as radiation resistant developed local recurrences with a median progression free interval of 9 months. Eighteen patients did not show local recurrences, and were regarded as a radiation-sensitive group. Using pretreatment paraffin-embedded tissues, we evaluated pAKT expression by immunohistochemistry. A significant association was found between the level of pAKT expression and local recurrence. Immunohistochemical staining for pAKT was significantly more frequent in the radiation-resistant than in the radiation-sensitive group (P ¼ 0.004). The mean progression-free survival was 86 months for patients with pAKT-negative staining (19 cases) and 44 months for patients with pAKT-positive expression (eight cases) (P ¼ 0.008). These results suggest that signalling from phosphatidylinositide 3-kinase/pAKT can lead to radiation resistance, and that evaluation of pAKT may be a prognostic marker for response to radiotherapy in LACC.

Increased phosphorylation of p70 S6 kinase is associated with HPV16 infection in cervical cancer and esophageal cancer

“…HPV16 E6 increases the phosphorylation of MAPK and MER (Chakrabarti et al, 2004). HPV16 E5 promotes the activation of EGFR and thus enhances the RAS/RAF/MAPK signalling cascade (Kim et al, 2006). Further investigation on why and how HPV oncoproteins preferentially target the different components in this pathway will be of great help for understanding HPV-induced tumourigenesis.…”

“…In our analysis, tumours were not classified by stages. In addition, Kim et al (2006) reported that Akt phosphorylation contributes to radioresistance in cervical cancer. A more detailed analysis is required to define the Akt phosphorylation-related disease stage and progression.…”

PKB/Akt promotes DSB repair in cancer cells through upregulating Mre11 expression following ionizing radiation

“…Data from numerous investigators show that an elevated level of Akt activity was associated with increased cellular resistance to radiation therapy (Brognard et al, 2001;Kim et al, 2006). Inhibition of phosphoinositide 3-kinase/Akt pathway leads to radiosensitization, such as glioblastomas, carcinoma of the breast, colon, bladder, prostate, head and neck and cervix (Gupta et al, 2002;Li et al, 2004;Altomare and Testa, 2005;Kim et al, 2005;Lee et al, 2006;Kao et al, 2007).…”

Stimulated PI3K-AKT Signaling Mediated through Ligand or Radiation-Induced EGFR Depends Indirectly, but not Directly, on Constitutive K-Ras Activity

“…signaling is an important cascade to promote cell survival in response to exogenous stress factors such as exposure to ionizing radiation (38,40,47). It has been shown for both in vitro and in vivo systems that radiation sensitivity of various tumor xenografts or cell lines overexpressing EGFR can efficiently be enhanced by blocking EGFR with the monoclonal anti-EGFR antibody C225 (48-51).…”

“…It seems to be clear that activation of AKT via PI3K occurs through phosphorylation by phosphoinositide-dependent kinase-1 and/or phosphoinositide-dependent kinase-2 at serine and threonine residues (Ser 472/473 , Thr 308 ). Several authors reported that especially phosphorylation of AKT at Ser 473 is associated with resistance to chemotherapy/ radiotherapy (36)(37)(38)(39)(40), and it has been proposed that activated AKT promotes survival of cells exposed to ionizing radiation through inhibition of apoptosis (41,42) or enhancement of DNA double-strand break repair (31).…”