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Edited by James E. Womack, Texas A&M University, College Station, TX, and approved August 19, 2014 (received for review January 21, 2014)
Significance
We tested the hypothesis that gelsolin (GSN) plays an important role in gynecological chemoresistance through the following: We provided strong evidence in support of GSN as an important etiologic factor in chemoresistance in vitro. We also determined the mechanism by which GSN exerts its prosurvival action. Our findings also suggest that the application of C-terminal GSN may represent a new therapeutic strategy for chemoresistant gynecologic cancer. We have also validated our in vitro findings with a clinical investigation that determines the relationship between GSN expression and cis-Diammine dichloroplatinium (II) sensitivity in human ovarian tumor. These findings agree with the notion that GSN plays a key role in the regulation of gynecological cell fate as reflected in chemoresistance.
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.
Footnotes
↵1M.R.A., P.-W.W., and Y.-F.H. contributed equally to this work.
- ↵2To whom correspondence may be addressed. Email: btsang{at}ohri.ca, dshieh{at}mail.ncku.edu.tw, or chougyn{at}mail.ncku.edu.tw.
Author contributions: M.R.A., P.-W.W., Y.-F.H., C.-Y.C., D.-B.S., and B.K.T. designed research; M.R.A., P.-W.W., Y.-F.H., and M.C. performed research; C.-Y.C., D.-B.S., and B.K.T. contributed new reagents/analytic tools; M.R.A., P.-W.W., Y.-F.H., C.-Y.C., D.-B.S., and B.K.T. analyzed data; and M.R.A., P.-W.W., and Y.-F.H. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1401166111/-/DCSupplemental.
Gelsolin confers chemoresistance
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