摘要
| 原文 | 英語 |
|---|---|
| 頁（從 - 到） | 2261-2272 |
| 頁數 | 12 |
| 期刊 | Biochimica et Biophysica Acta - Molecular Cell Research |
| 卷 | 1853 |
| 發行號 | 10 |
| DOIs | |
| 出版狀態 | 已發佈 - 十月 1 2015 |
指紋
ASJC Scopus subject areas
- Cell Biology
- Molecular Biology
引用此文
Targeting of multiple oncogenic signaling pathways by Hsp90 inhibitor alone or in combination with berberine for treatment of colorectal cancer. / Su, Yen-Hao; Tang, Wan Chun; Cheng, Ya Wen; Sia, Peik; Huang, Chi Chen; Lee, Yi Chao; Jiang, Hsin Yi; Wu, Ming Heng; Lai, I. Lu; Lee, Jun Wei; Lee, Kuen Haur.
於: Biochimica et Biophysica Acta - Molecular Cell Research, 卷 1853, 編號 10, 01.10.2015, p. 2261-2272.研究成果: 雜誌貢獻 › 文章
}
TY - JOUR
T1 - Targeting of multiple oncogenic signaling pathways by Hsp90 inhibitor alone or in combination with berberine for treatment of colorectal cancer
AU - Su, Yen-Hao
AU - Tang, Wan Chun
AU - Cheng, Ya Wen
AU - Sia, Peik
AU - Huang, Chi Chen
AU - Lee, Yi Chao
AU - Jiang, Hsin Yi
AU - Wu, Ming Heng
AU - Lai, I. Lu
AU - Lee, Jun Wei
AU - Lee, Kuen Haur
PY - 2015/10/1
Y1 - 2015/10/1
N2 - There is a wide range of drugs and combinations under investigation and/or approved over the last decade to treat colorectal cancer (CRC), but the 5-year survival rate remains poor at stages II-IV. Therefore, new, more-efficient drugs still need to be developed that will hopefully be included in first-line therapy or overcome resistance when it appears, as part of second- or third-line treatments in the near future. In this study, we revealed that heat shock protein 90 (Hsp90) inhibitors have high therapeutic potential in CRC according to combinative analysis of NCBI's Gene Expression Omnibus (GEO) repository and chemical genomic database of Connectivity Map (CMap). We found that second generation Hsp90 inhibitor, NVP-AUY922, significantly downregulated the activities of a broad spectrum of kinases involved in regulating cell growth arrest and death of NVP-AUY922-sensitive CRC cells. To overcome NVP-AUY922-induced upregulation of survivin expression which causes drug insensitivity, we found that combining berberine (BBR), a herbal medicine with potency in inhibiting survivin expression, with NVP-AUY922 resulted in synergistic antiproliferative effects for NVP-AUY922-sensitive and -insensitive CRC cells. Furthermore, we demonstrated that treatment of NVP-AUY922-insensitive CRC cells with the combination of NVP-AUY922 and BBR caused cell growth arrest through inhibiting CDK4 expression and induction of microRNA-296-5p (miR-296-5p)-mediated suppression of Pin1-β-catenin-cyclin D1 signaling pathway. Finally, we found that the expression level of Hsp90 in tumor tissues of CRC was positively correlated with CDK4 and Pin1 expression levels. Taken together, these results indicate that combination of NVP-AUY922 and BBR therapy can inhibit multiple oncogenic signaling pathways of CRC.
AB - There is a wide range of drugs and combinations under investigation and/or approved over the last decade to treat colorectal cancer (CRC), but the 5-year survival rate remains poor at stages II-IV. Therefore, new, more-efficient drugs still need to be developed that will hopefully be included in first-line therapy or overcome resistance when it appears, as part of second- or third-line treatments in the near future. In this study, we revealed that heat shock protein 90 (Hsp90) inhibitors have high therapeutic potential in CRC according to combinative analysis of NCBI's Gene Expression Omnibus (GEO) repository and chemical genomic database of Connectivity Map (CMap). We found that second generation Hsp90 inhibitor, NVP-AUY922, significantly downregulated the activities of a broad spectrum of kinases involved in regulating cell growth arrest and death of NVP-AUY922-sensitive CRC cells. To overcome NVP-AUY922-induced upregulation of survivin expression which causes drug insensitivity, we found that combining berberine (BBR), a herbal medicine with potency in inhibiting survivin expression, with NVP-AUY922 resulted in synergistic antiproliferative effects for NVP-AUY922-sensitive and -insensitive CRC cells. Furthermore, we demonstrated that treatment of NVP-AUY922-insensitive CRC cells with the combination of NVP-AUY922 and BBR caused cell growth arrest through inhibiting CDK4 expression and induction of microRNA-296-5p (miR-296-5p)-mediated suppression of Pin1-β-catenin-cyclin D1 signaling pathway. Finally, we found that the expression level of Hsp90 in tumor tissues of CRC was positively correlated with CDK4 and Pin1 expression levels. Taken together, these results indicate that combination of NVP-AUY922 and BBR therapy can inhibit multiple oncogenic signaling pathways of CRC.
KW - Berberine
KW - Colorectal cancer
KW - Connectivity Map
KW - Heat shock protein 90 inhibitor
KW - MiR-296-5p
UR - http://www.scopus.com/inward/record.url?scp=84938151056&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84938151056&partnerID=8YFLogxK
U2 - 10.1016/j.bbamcr.2015.05.012
DO - 10.1016/j.bbamcr.2015.05.012
M3 - Article
VL - 1853
SP - 2261
EP - 2272
JO - Biochimica et Biophysica Acta - Molecular Cell Research
JF - Biochimica et Biophysica Acta - Molecular Cell Research
SN - 0167-4889
IS - 10
ER -