Sulforaphane inhibits proliferation and invasive activity of everolimus-resistant kidney cancer cells in vitro

  • Although the mechanistic target of rapamycin (mTOR) inhibitor, everolimus, has improved the outcome of patients with renal cell carcinoma (RCC), improvement is temporary due to the development of drug resistance. Since many patients encountering resistance turn to alternative/complementary treatment options, an investigation was initiated to evaluate whether the natural compound, sulforaphane (SFN), influences growth and invasive activity of everolimus-resistant (RCCres) compared to everolimus-sensitive (RCCpar) RCC cell lines in vitro. RCC cells were exposed to different concentrations of SFN and cell growth, cell proliferation, apoptosis, cell cycle, cell cycle regulating proteins, the mTOR-akt signaling axis, adhesion to human vascular endothelium and immobilized collagen, chemotactic activity, and influence on surface integrin receptor expression were investigated. SFN caused a significant reduction in both RCCres and RCCpar cell growth and proliferation, which correlated with an elevation in G2/M- and S-phase cells. SFN induced a marked decrease in the cell cycle activating proteins cdk1 and cyclin B and siRNA knock-down of cdk1 and cyclin B resulted in significantly diminished RCC cell growth. SFN also modulated adhesion and chemotaxis, which was associated with reduced expression of the integrin subtypes α5, α6, and β4. Distinct differences were seen in RCCres adhesion and chemotaxis (diminished by SFN) and RCCpar adhesion (enhanced by SFN) and chemotaxis (not influenced by SFN). Functional blocking of integrin subtypes demonstrated divergent action on RCC binding and invasion, depending on RCC cell sensitivity to everolimus. Therefore, SFN administration could hold potential for treating RCC patients with established resistance towards everolimus.

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Author:Eva JüngelORCiDGND, Sebastian Maxeiner, Jochen RutzGND, Saira Justin, Frederik RoosGND, Wael Y. Khoder, Igor TsaurORCiDGND, Karen Nelson, Wolf Otto BechsteinORCiDGND, Axel HaferkampGND, Roman A. BlahetaORCiD
URN:urn:nbn:de:hebis:30:3-458404
DOI:https://doi.org/10.18632/oncotarget.13421
ISSN:1949-2553
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/27863441
Parent Title (English):OncoTarget
Publisher:Impact Journals LLC
Place of publication:[S.l.]
Document Type:Article
Language:English
Year of Completion:2016
Date of first Publication:2016/11/17
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2018/03/08
Tag:complementary and alternative medicine; invasion; proliferation; renal cell carcinoma; sulforaphane
Volume:7
Issue:51
Page Number:12
First Page:85208
Last Page:55219
Note:
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
HeBIS-PPN:432109668
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 3.0