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Tropomodulin 3 Overexpression as a Marker for Platinum Resistance and Immune Infiltration in Ovarian Cancer
Published on: August 2, 2024
Modulation of survival pathways in ovarian carcinoma cell lines resistant to platinum compounds
Valentina Benedetti1, Paola Perego, Giovanni Luca Beretta
1Department of Experimental Oncology and Laboratories, Istituto Nazionale Tumori, Via Venezian 1, Milan, Italy.
Abstract:
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.
Insights
Resistance to platinum drugs in ovarian cancer involves altered survival pathways. Epidermal growth factor receptor (EGFR) signaling and related kinases like ERK1/2 are implicated, affecting sensitivity to EGFR inhibitors such as gefitinib.
Area of Science:
- Molecular Oncology
- Cancer Cell Signaling
- Drug Resistance Mechanisms
Background:
- Cytotoxic stress activates signaling pathways influencing cell survival and death.
- Alterations in these pathways are relevant to the development of platinum-resistant phenotypes in cancer.
- Ovarian carcinoma cell lines are models for studying platinum resistance.
Purpose of the Study:
- To investigate the cellular response of ovarian carcinoma cell lines to gefitinib, an epidermal growth factor receptor (EGFR) inhibitor.
- To compare the response in cisplatin- and oxaliplatin-resistant sublines versus the parental cell line.
- To elucidate the role of EGFR signaling and downstream pathways in platinum drug resistance.
Main Methods:
- Utilized ovarian carcinoma cell lines, including platinum-resistant sublines (IGROV-1/Pt1 and IGROV-1/OHP).
- Assessed sensitivity to gefitinib and apoptosis.
- Investigated the phosphorylation status of EGFR, Akt, ERK1/2, and p38 kinases.
- Examined the effect of MEK1/2 inhibitor U0126 on gefitinib sensitivity and EGFR localization.
Main Results:
- Resistant sublines showed decreased sensitivity to gefitinib and resistance to apoptosis.
- Gefitinib inhibited EGFR phosphorylation, but phospho-ERK1/2 levels increased in resistant cells, correlating with reduced sensitivity to U0126.
- U0126 pretreatment restored gefitinib sensitivity in resistant cells.
- Phospho-p38 was upregulated in resistant sublines, associated with EGFR internalization.
- Gefitinib was less effective in inhibiting ERK1/2 and Akt phosphorylation in resistant cells.
Conclusions:
- Development of platinum drug resistance in ovarian cancer is linked to multiple molecular alterations.
- Deregulation of EGFR-activated survival pathways contributes to reduced cellular response to gefitinib in resistant cells.
- Aberrant activation of ERK1/2 and p38 pathways plays a role in platinum resistance.
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