2,4-Bis(4-hydroxybenzyl)phenol inhibits heat shock transcription factor 1 and sensitizes lung cancer cells to conventional anticancer modalities.

Abstract

Heat shock factor 1 (HSF1) is a transcription factor that regulates expression of heat shock protein (HSP) genes in response to stress. HSPs are expressed at high levels in a wide range of tumors. It has been reported that HSF1 and HSPs are associated closely in tumorigenesis. In the present study, a screen was performed using a luciferase reporter under the control of a heat shock element to find inhibitors of HSF1 activity, and 2,4-bis(4-hydroxybenzyl)phenol (1), isolated from the rhizomes of Gastrodia elata, was identified as an active compound. This substance effectively inhibited HSF1 activity and decreased levels of HSP27 and HSP70. Compound 1 induced the degradation of HSF1 protein through dephosphorylation of HSF1 on S326, which decreases HSF1 protein stability. In addition, 1 also induced growth arrest and apoptosis of NCI-H460 human lung cancer cells. Markers of apoptosis, such as cleaved PARP and cleaved caspase-3, were detected after treatment with 1. Furthermore, cotreatment with 1 and conventional anticancer modalities such as paclitaxel, cisplatin, or ionizing radiation potentiated their effects on lung cancer cells. These results suggest that inhibition of HSF1 by 1 may help overcome resistance to conventional anticancer modalities in HSF1-overexpressed cancer cells.

• Authors: Taesook Yoon, Ga-Young Kang, Ah-Reum Han, Eun-Kyoung Seo, Yun-Sil Lee
• Journal: Journal of natural products (J Nat Prod) Vol. 77 Issue 5 Pg. 1123-9 (May 23 2014) ISSN: 1520-6025 [Electronic] United States
• PMID: 24746225 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Benzhydryl Compounds
• DNA-Binding Proteins
• HSF1 protein, human
• HSP27 Heat-Shock Proteins
• HSP70 Heat-Shock Proteins
• Heat Shock Transcription Factors
• Phenols
• Transcription Factors
• 2,4-bis(4-hydroxybenzyl)phenol
• Caspase 3

Topics

• Apoptosis (drug effects)
• Benzhydryl Compounds (chemistry, pharmacology)
• Caspase 3 (metabolism)
• DNA-Binding Proteins (antagonists & inhibitors)
• HSP27 Heat-Shock Proteins (analysis, genetics, metabolism)
• HSP70 Heat-Shock Proteins (analysis, genetics, metabolism)
• Heat Shock Transcription Factors
• Humans
• Lung Neoplasms
• Molecular Structure
• Phenols (chemistry, pharmacology)
• Polymerase Chain Reaction
• Transcription Factors (antagonists & inhibitors)