Publications

Authors:

Benedetti, V; Perego, P; Beretta, Gl; Corna, E; Tinelli, S; Righetti, Sc; Leone, Roberto; Apostoli, P; Lanzi, C; Zunino, F.

Title:

Modulation of survival pathways in ovarian carcinoma cell lines resistant to platinum compounds

Year:

2008

Type of item:

Articolo in Rivista

Tipologia ANVUR:

Articolo su rivista

Language:

Inglese

Format:

A Stampa

Referee:

Sì

Name of journal:

MOLECULAR CANCER THERAPEUTICS

ISSN of journal:

1535-7163

N° Volume:

7

Number or Folder:

3

Page numbers:

679-687

Keyword:

Ovarian cancer; platinum; resistance

Short description of contents:

Because cytotoxic stress elicits various signaling pathways that may be implicated in cell survival or cell death, their alterations may have relevance in the development of platinum-resistant phenotype. Thus, in the present study, we investigated cell response to the epidermal growth factor receptor (EGFR) inhibitor gefitinib of ovarian carcinoma cell lines, including cells selected for resistance to cisplatin (IGROV-1/Pt1) and oxaliplatin (IGROV-1/OHP). Resistant sublines exhibited a marked decrease in sensitivity to gefitinib and resistance to apoptosis. Gefitinib was capable of inhibiting the phosphorylation of EGFR in all the studied cell lines. The Akt and extracellular signal-regulated kinase 1/2 (ERK1/2) kinases, which act downstream of EGFR, were constitutively active in the three cell lines, but phospho-ERK1/2 levels were increased in the two resistant sublines. This feature was associated with reduced sensitivity to the MEK1/2 inhibitor U0126. Pretreatment of resistant cells with U0126 resulted in restoration of sensitivity to gefitinib. Gefitinib was more effective in inhibiting ERK1/2 and Akt phosphorylation in IGROV-1 cells than in IGROV-1/OHP and IGROV-1/Pt1 cells. Phospho-p38 was up-regulated in the resistant sublines, indicating the concomitant activation of distinct mitogen-activated protein kinases. The up-regulation of phospho-p38 was associated with a peculiar localization of EGFR, which, in resistant sublines, was mainly internalized. In conclusion, our results indicate that the development of resistance to platinum drugs is associated with multiple alterations including deregulation of survival pathways activated by EGFR resulting in a reduced cellular response to gefitinib

Product ID:

40999

Handle IRIS:

11562/317499

Deposited On:

March 8, 2012

Last Modified:

November 15, 2022

Bibliographic citation:

Benedetti, V; Perego, P; Beretta, Gl; Corna, E; Tinelli, S; Righetti, Sc; Leone, Roberto; Apostoli, P; Lanzi, C; Zunino, F., Modulation of survival pathways in ovarian carcinoma cell lines resistant to platinum compounds «MOLECULAR CANCER THERAPEUTICS» , vol. 7 , n. 3 , 2008 , pp. 679-687

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