Journal
ONCOTARGET
Volume 8, Issue 54, Pages 92032-92042Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.20734
Keywords
silibinin; bladder cancer; KRAS; PI3K; long non-coding RNA
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Funding
- Astellas Foundation for Research on Metabolic Disorders fellowship - Astellas Pharma, Inc
- National Institutes of Health [R01CA196848, RO1CA138642, RO1CA160079, RO1CA199694, RO1CA184966]
- Veterans Affairs Program [BX001604]
- Veterans Affairs Merit Review grants
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Silibinin is the major active constituent of silymarin, an extract of milk thistle seeds. Silibinin has been shown to have significant anti-cancer effects in a variety of malignancies. However, the molecular mechanisms of silibinin action in bladder cancer have not been studied extensively. In the present study, we found that silibinin (10 mu M) significantly suppressed proliferation, migration, invasion and induced apoptosis of T24 and UM-UC-3 human bladder cancer cells. Silibinin down-regulated the actin cytoskeleton and phosphatidylinositide 3-kinase (PI3K)/Akt signaling pathways in these cancer cell lines. These pathways were found to crosstalk through RAS cascades. We found that silibinin suppressed levels of trimethylated histone H3 lysine 4 and acetylated H3 at the KRAS promoter. Furthermore, silibinin targets long non-coding RNA: HOTAIR and ZFAS1, which are known to play roles as oncogenic factors in various cancers. This study shows that silibinin exerts anti-cancer effects through down-regulation of actin cytoskeleton and PI3K/Akt pathways and thus suppresses bladder cancer growth and progression.
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