Dorsomorphin induces cancer cell apoptosis and sensitizes cancer cells to HSP90 and proteasome inhibitors by reducing nuclear heat shock factor 1 levels

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.

Quantitative analysis of planation surfaces of the upper Yangtze River in the Sichuan-Yunnan Region, Southwest China

Identification of the planation surfaces (PSs)is key for utilizing them as a reference in studying the long- term geomorphological evolution of the Upper Yangtze River Basin in the Sichuan-Yurman region,Southwest China.Using a combined method of DEM-based fuzzy logic and topographic and fiver profiles analysis and based on a comprehensive analysis of four morphometfic parameters:slope,curvature,terrain raggedness index, and relative height,we established the relevant fuzzy membership functions,and then calculated the membership degree (MD)of the study area.Results show that patches with a MD>80% and an area>0.4 km^2 correspond well to the results of Google Earth and field investigation,representing the PS remnants.They consist of 1764 patches with an altitude,area,mean slope,and relief of mostly 2000-2500 m above sea level (asl),0-10 km^2,4°-9°,0-500 m,respectively,covering 9.2% of the study area's landscape,dipping to southeast,decreasing progressively from northwest to southeast in altitude,and with no clear relation between each patch's altitude and slope,or relief.All these results indicate that they are remnants of once regionally continuous PSs which were deformed by both the lower crust flow and the faults in upper crust,and dissected by the network of Upper Yangtze River.Additionally,topographic and river profiles analysis show that three PSs (PS1-PS3)well developed along the main valleys in the Yongren-Huili region, indicating several phases of uplift then planation during the Late Cenozoic era.Based on the incision amount deduced from projection of relict river profiles on PSs, together with erosion rates,breakup times of the PS 1,PS2,and PS3 were estimated to be 3.47 Ma,2.19 Ma,and 1.45 Ma,respectively,indicating appearance of modem Upper Yangtze River valley started between the Pliocene to early Pleistocene.