Abstract

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.

Original languageEnglish
Pages (from-to)2261-2272
Number of pages12
JournalBiochimica et Biophysica Acta - Molecular Cell Research
Volume1853
Issue number10
DOIs
Publication statusPublished - Oct 1 2015

Fingerprint

Berberine
HSP90 Heat-Shock Proteins
Colorectal Neoplasms
Chemical Databases
Catenins
5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide
Herbal Medicine
Cyclin D1
Drug Combinations
Growth
MicroRNAs
Pharmaceutical Preparations
Phosphotransferases
Up-Regulation
Therapeutics
Down-Regulation
Gene Expression

Keywords

  • Berberine
  • Colorectal cancer
  • Connectivity Map
  • Heat shock protein 90 inhibitor
  • MiR-296-5p

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

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.

In: Biochimica et Biophysica Acta - Molecular Cell Research, Vol. 1853, No. 10, 01.10.2015, p. 2261-2272.

Research output: Contribution to journalArticle

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abstract = "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.",
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AU - Tang, Wan Chun

AU - Cheng, Ya Wen

AU - Sia, Peik

AU - Huang, Chi Chen

AU - Lee, Yi Chao

AU - Jiang, Hsin Yi

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AU - Lai, I. Lu

AU - Lee, Jun Wei

AU - Lee, Kuen Haur

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