Cell fate regulation by gelsolin in human gynecologic cancers.

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.

• Authors: Mohammad R Abedini, Pei-Wen Wang, Yu-Fang Huang, Mingju Cao, Cheng-Yang Chou, Dar-Bin Shieh, Benjamin K Tsang
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 111 Issue 40 Pg. 14442-7 (Oct 07 2014) ISSN: 1091-6490 [Electronic] United States
• PMID: 25246592 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• CASP8 and FADD-Like Apoptosis Regulating Protein
• Gelsolin
• Repressor Proteins
• ITCH protein, human
• Ubiquitin-Protein Ligases
• Cisplatin

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Blotting, Western
• CASP8 and FADD-Like Apoptosis Regulating Protein (metabolism)
• Cell Line, Tumor
• Cisplatin (pharmacology)
• Cystadenocarcinoma, Serous (genetics, metabolism, pathology)
• Down-Regulation (drug effects)
• Drug Resistance, Neoplasm
• Female
• Gelsolin (genetics, metabolism)
• Gene Expression Regulation, Neoplastic
• Humans
• Microscopy, Confocal
• Middle Aged
• Models, Biological
• Ovarian Neoplasms (genetics, metabolism, pathology)
• Prognosis
• Protein Binding (drug effects)
• RNA Interference
• Repressor Proteins (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Survival Analysis
• Ubiquitin-Protein Ligases (metabolism)