Silibinin suppresses bladder cancer through down-regulation of actin cytoskeleton and PI3K/Akt signaling pathways.

Mitsuho Imai-Sumida,Takeshi Chiyomaru,Soichiro Yamamura,Rajvir Dahiya,Hannah Nip,Sharanjot Saini,Yuichiro Tanaka,Shahana Majid

doi:10.18632/oncotarget.20734

Mitsuho Imai-Sumida, Takeshi Chiyomaru + Show 6 more

Open Access

https://doi.org/10.18632/oncotarget.20734

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Abstract

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 μM) 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.

Highlights

Silibinin is a polyphenolic flavonolignan and is a major active component in silymarin, an extract of milk thistle (Silybum marianum) seeds
We found that silibinin suppressed levels of trimethylated histone H3 lysine 4 and acetylated H3 at the KRAS promoter
Silibinin inhibited UM-UC-3 cell proliferation by 39% (5 μM), 69% (10 μM) and 77% (25 μM) at 48 hours (Figure 1B). These results show that silibinin significantly suppresses the proliferation of these bladder cancer cell lines in a dose-dependent manner

Summary

Introduction

Silibinin is a polyphenolic flavonolignan and is a major active component in silymarin, an extract of milk thistle (Silybum marianum) seeds. Silibinin has been shown to have significant anti-cancer effects in a variety of cancer types [1], including prostate [1,2,3], bladder [4, 5], kidney [6, 7], skin [8, 9], pancreas [10], breast [3, 11], lung [12,13,14] and colon [15, 16] cancers. In the United States, bladder cancer is the 4th and 9th most common cancer in men and women respectively, comprising 7% of all cancer cases in 2014. More than 50,000 men and 16,000 women are newly diagnosed with bladder cancer in the United States in 2014 [19]

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