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Updated: Apr 23, 2026
Obtaining Cancer Stem Cell Spheres from Gynecological and Breast Cancer Tumors
Published on: March 1, 2020
Cell fate regulation by gelsolin in human gynecologic cancers
Mohammad R Abedini1, Pei-Wen Wang2, Yu-Fang Huang3
1Departments of Obstetrics and Gynaecology and Cellular and Molecular Medicine, Interdisciplinary School of Health Sciences, University of Ottawa, Ottawa, ON, Canada K1H 8L6; Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada K1H 8L6; Cellular and Molecular Medicine Research Center, Department of Pharmacology, Birjand University of Medical Sciences, Birjand 97178, Iran;
Abstract:
Chemoresistance is a major hurdle in cancer treatment. Down-regulation of apoptosis pathways is one of the key determinants for chemoresistance. Here, we report higher gelsolin (GSN) levels in chemoresistant gynecological cancer cells compared with their sensitive counterparts. cis-Diammine dichloroplatinium (II) (CDDP)-induced GSN down-regulation is associated with its cleavage and apoptosis. Although the C-terminal GSN fragment (C-GSN) sensitized chemoresistant cells to CDDP, intact GSN and its N-terminal fragment (N-GSN) attenuated this response. GSN silencing also facilitated CDDP-induced apoptosis in chemoresistant cells. In contrast, intact GSN (I-GSN) was prosurvival in the presence of CDDP through a FLICE-like inhibitory protein (FLIP)-Itch interaction. This interaction was colocalized in the perinuclear region that could be dissociated by CDDP in sensitive cells, thereby inducing FLIP ubiquitination and degradation, followed by apoptosis. In resistant cells, GSN was highly expressed and CDDP failed to abolish the I-GSN-FLIP-Itch interaction, resulting in the dysregulation of the downstream responses. In addition, we investigated the association between GSN expression in ovarian serous adenocarcinoma and progression free survival and overall survival, as well as clinical prognosis. GSN overexpression was significantly associated with more aggressive behavior and more cancer deaths and supported our hypothesis that high GSN expression confers chemoresistance in cancer cells by altering the GSN-FLIP-Itch interaction. These findings are in agreement with the notion that GSN plays an important role in the regulation of gynecological cell fate as reflected in dysregulation in chemosensitivity.
Insights
High gelsolin (GSN) levels promote chemoresistance in gynecological cancers by disrupting apoptosis pathways. GSN fragments and silencing impact sensitivity to chemotherapy, offering potential therapeutic targets.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Chemoresistance is a significant challenge in cancer therapy, often linked to altered apoptosis.
- Gelsolin (GSN) levels and function are implicated in cellular responses to chemotherapy.
Purpose of the Study:
- To investigate the role of gelsolin (GSN) in chemoresistance of gynecological cancer cells.
- To elucidate the molecular mechanisms by which GSN influences sensitivity to cis-Diammine dichloroplatinium (II) (CDDP).
Main Methods:
- Comparative analysis of GSN levels in chemoresistant versus sensitive gynecological cancer cells.
- Assessment of GSN fragments (intact, N-terminal, C-terminal) and GSN silencing effects on CDDP-induced apoptosis.
- Investigation of the interaction between GSN, FLICE-like inhibitory protein (FLIP), and Itch in response to CDDP.
- Correlation analysis of GSN expression with clinical prognosis in ovarian serous adenocarcinoma.
Main Results:
- Chemoresistant cells exhibited higher gelsolin (GSN) levels.
- CDDP-induced GSN down-regulation and cleavage promoted apoptosis; C-terminal GSN fragment sensitized cells, while intact GSN and N-terminal fragment attenuated sensitivity.
- GSN silencing enhanced CDDP-induced apoptosis in resistant cells.
- Intact GSN (I-GSN) conferred prosurvival effects via a FLIP-Itch interaction, which was dysregulated in resistant cells.
- High GSN expression correlated with aggressive cancer behavior and poorer survival in ovarian cancer patients.
Conclusions:
- Gelsolin (GSN) plays a critical role in conferring chemoresistance in gynecological cancers.
- Altered GSN expression and its interaction with FLIP-Itch dysregulate apoptosis, impacting treatment outcomes.
- Targeting GSN or its interactions may represent a strategy to overcome chemoresistance.
