Modulation of PI3K/Akt pathway by E1a mediates sensitivity to cisplatin

Viniegra, Juan Guinea; Losa, Javier Hernández; Sanchez-Arevalo, Victor Javier; Cobo, Carlos Parada; Soria, Victor Manuel Fernández; Cajal, Santiago Ramón y; Sánchez‐Prieto, Ricardo

doi:10.1038/sj.onc.1205934

Cited by 36 publications

(33 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A similar finding was shown with renal tubular epithelial cells, where PKB/Akt was found to inhibit the activation of caspases (Kaushal et al, 2001). Moreover, a recent study showed that chemosensitivity induced by adenoviral E1a gene expression is owing to the inhibition of PKB/Akt activation upon Cisplatin treatment (Viniegra et al, 2002). Our study shows that PKB/Akt is activated by Cisplatin, as measured by T308 phosphorylation, in ovarian, pancreatic and breast cancer cell lines, as well as in Rat1 fibroblasts, indicating that PKB/ Akt activation by Cisplatin is a widespread phenomenon (Figure 1).…”

Section: P38 Phosphorylates the Egfr On Threonine 669supporting

confidence: 60%

Cisplatin induces PKB/Akt activation and p38MAPK phosphorylation of the EGF receptor

2006

View full text Add to dashboard Cite

Cisplatin is an effective DNA-damaging antitumor agent employed for the treatment of various human cancers. In this study, we report that Cisplatin activates PKB/Akt in several cancer cell lines and that this activation is mediated by EGFR, Src and PI3-kinase. Inhibition of PI3-kinase activity decreases the survival of the cells exposed to Cisplatin, suggesting that Cisplatin-induced PKB/Akt activation may lead to Cisplatin resistance. While investigating the EGFR-dependent PKB/Akt activation in MDA-MB-468 cells, we found that the EGFR receptor undergoes a gel mobility shift upon Cisplatin treatment, which is mediated by p38MAPK . An EGFR, in which threonine 669 was mutated to alanine (A669), is phosphorylated by p38 MAPK to a much lesser extent, suggesting that threonine 669 is a p38 phosphorylation site. We found that Cisplatin induces EGFR internalization, which is mediated by p38 MAPK-dependent phosphorylation of the receptor on threonine 669. Our results identify the EGFR as a new substrate of p38 and identify threonine 669 as a new phosphorylation site that regulates EGFR internalization. Together, these results suggest that Cisplatin has side effects, which may alter the signaling pattern of cancer cells and modulate the desired effects of Cisplatin treatment.

show abstract

Section: P38 Phosphorylates the Egfr On Threonine 669supporting

confidence: 60%

Cisplatin induces PKB/Akt activation and p38MAPK phosphorylation of the EGF receptor

2006

View full text Add to dashboard Cite

show abstract

“…This raises the possibility that transformation by viral oncogenes may initiate a DNA-damage response triggering down-regulation of MCL-1 and susceptibility to apoptosis. E1A expression sensitizes cells to apoptosis induced by DNA-damaging agents (Sanchez-Prieto et al 1996;Brader et al 1997;Shao et al 1997;Stiewe et al 2000;Viniegra et al 2002), as does specific knock-down of MCL-1 (Nijhawan et al 2003). This priming of apoptosis by E1A may require adenovirus to encode an antiapoptotic function to sustain viability during oncogenesis.…”

Section: E1a Provokes a Dna Damage Response That Results In Mcl-1 Elimentioning

confidence: 99%

DNA damage response and MCL-1 destruction initiate apoptosis in adenovirus-infected cells

Cuconati¹,

Mukherjee²,

Perez³

et al. 2003

Genes Dev.

295

289

View full text Add to dashboard Cite

show abstract

“…40 Therefore, cells with high Akt-3 levels or reduced PTEN are more resistant to chemotherapeutic agents. [15][16][17][40][41][42][43] There is a significant negative correlation between low cellular levels of ER-a, and PTEN on one side and elevated Akt-3/ PK-B on the other. 37,[44][45][46] Functional association between PTEN and estradiol is supported by the observation that in knockout mice with a mammaryspecific deletion of the PTEN gene, exposure to estradiol enhanced development of mammary tumor early in life.…”

Section: Discussionmentioning

confidence: 99%

Reduced PTEN expression predicts relapse in patients with breast carcinoma treated by tamoxifen

et al. 2005

View full text Add to dashboard Cite

Tamoxifen treatment substantially improves the 10-year survival of women with estrogen-receptor (ER)-apositive tumors. However, approximately one-third of all breast cancer patients with ER-a-positive tumors progress on antiestrogen therapy. The molecular mechanism(s) involved in antiestrogen-resistant phenotype of breast carcinoma is not completely understood. The PTEN (phosphatase and tensin homolog deleted on chromosome Ten) gene is a novel candidate tumor suppressor that plays an important role in cell cycle regulation and apoptosis by regulating Protein kinase-B/Akt activity. Previous studies have shown that PTEN downregulation in breast cancer is associated with high-grade tumor, distant metastases and poorer diseasefree survival. Decreased PTEN and/or increased protein kinase B/Akt activity in breast cancer cells has recently been associated with resistance to tamoxifen-induced apoptosis. In this study, we have evaluated PTEN expression by immunohistochemistry in 100 tamoxifen-treated ER-a-positive breast cancer patients. Reduced PTEN protein expression was associated with shorter relapse-free survival. When stage I patients were analyzed separately, reduced PTEN expression was a strong predictor of both, shorter relapse-free survival and shorter disease-specific survival. An association of reduced PTEN expression with shorter relapse-free survival and disease-specific survival in stage I patients was still observed after stratification by stage, axillary lymph node status, tumor size, grade, and expression of ER-a, progesterone receptor, and Her-2/neu. In summary, our results showed a strong association between downregulation of PTEN expression in ER-a-positive tumors and failure to tamoxifen treatment.

show abstract

Modulation of PI3K/Akt pathway by E1a mediates sensitivity to cisplatin

Cited by 36 publications

References 21 publications

Cisplatin induces PKB/Akt activation and p38MAPK phosphorylation of the EGF receptor

Cisplatin induces PKB/Akt activation and p38MAPK phosphorylation of the EGF receptor

DNA damage response and MCL-1 destruction initiate apoptosis in adenovirus-infected cells

Reduced PTEN expression predicts relapse in patients with breast carcinoma treated by tamoxifen

Contact Info

Product

Resources

About