PT  - JOURNAL ARTICLE
AU  - Na Li
AU  - Ting Wang
AU  - Zongmeng Li
AU  - Xiaoli Ye
AU  - Bo Deng
AU  - Shu Zhuo
AU  - Pengle Yao
AU  - Mengmei Yang
AU  - Hong Mei
AU  - Xiaofang Chen
AU  - Tengfei Zhu
AU  - Shiting Chen
AU  - Hui Wang
AU  - Jiming Wang
AU  - Yingying Le
TI  - Dorsomorphin induces cancer cell apoptosis and sensitizes cancer cells to HSP90 and proteasome inhibitors by reducing nuclear heat shock factor 1 levels
AID  - 10.20892/j.issn.2095-3941.2018.0235
DP  - 2019 May 01
TA  - Cancer Biology and Medicine
PG  - 220--235
VI  - 16
IP  - 2
4099  - http://www.cancerbiomed.org/content/16/2/220.short
4100  - http://www.cancerbiomed.org/content/16/2/220.full
SO  - Cancer Biol Med2019 May 01; 16
AB  - Objective Heat shock factor 1 (HSF1), a transcriptional regulator of heat shock proteins (HSPs), is an attractive therapeutic target for cancer. However, only a few HSF1 inhibitors have been identified so far.Methods The mRNA and protein levels of HSF1, HSPs, cleaved PARP, and phosphorylated HSF1 were examined by real-time PCR and Western blot. Forced expression, RNA interference, and immunofluorescence assay were used for mechanistic studies. Cell viability and apoptosis were measured by WST-8 assay and flow cytometry, respectively. Xenograft studies were performed in nude mice to evaluate the effect of dorsomorphin and an HSP90 inhibitor on tumor growth.Results Dorsomorphin suppressed multiple stimuli-induced and constitutive HSPs expression in cancer cells. Mechanistic studies revealed that dorsomorphin reduced heat-induced HSP expression independent of adenosine monophosphate activated protein kinase. Dorsomorphin reduced heat-stimulated HSF1 Ser320 phosphorylation and nuclear translocation, as well as resting nuclear HSF1 levels in cancer cells. Dorsomorphin induced cancer cell apoptosis by inhibiting HSF1 expression. A structure-activity study revealed that the 4-pyridyl at the 3-site of the pyrazolo [1, 5-a]pyrimidine ring is critical for the anti-HSF1 activities of dorsomorphin. Dorsomorphin sensitized cancer cells to HSP90 and proteasome inhibitors and inhibited HSP70 expression induced by these inhibitors in vitro. In tumor-bearing nude mice, dorsomorphin enhanced HSP90 inhibitor-induced cancer cell apoptosis, tumor growth inhibition, and HSP70 expression.Conclusions Dorsomorphin is an HSF1 inhibitor. It induces cancer cell apoptosis, sensitizes cancer cells to both HSP90 and proteasome inhibitors, and suppresses HSP upregulation by these drugs, which may prevent the development of drug resistance. Hence, dorsomorphin and its derivates may serve as potential precursors for developing drugs against cancer.