Mitochondrial Hsp90s suppress calcium-mediated stress signals propagating from mitochondria to the ER in cancer cells

Background: Resistance to cell death in the presence of stressful stimuli is one of the hallmarks of cancer cells acquired during multistep tumorigenesis, and knowledge of the molecular mechanism of stress adaptation can be exploited to develop cancer-selective therapeutics. Mitochondria and the endoplasmic reticulum (ER) are physically interconnected organelles that can sense and exchange various stress signals. Although there have been many studies on stress propagation from the ER to mitochondria, reverse stress signals originating from mitochondria have not been well reported.Methods: After inactivation of the proteins by pharmacologic and genetic methods, the signal pathways were analyzed by fluorescence microscopy, flow cytometry, MTT assay, and western blotting. A mouse xenograft model was used to examine synergistic anticancer activity and the action mechanism of drugs in vivo.Results: We show in this study that mitochondrial heat shock protein 90 (Hsp90) suppresses mitochondria-initiated calcium-mediated stress signals propagating into the ER in cancer cells. Mitochondrial Hsp90 inhibition triggers the calcium signal by opening the mitochondrial permeability transition pore and, in turn, the ER ryanodine receptor, via calcium-induced calcium release. Subsequent depletion of ER calcium activates unfolded protein responses in the ER lumen, thereby increasing the expression of a pro-apoptotic transcription factor, CEBP homologous protein (CHOP). Combined treatment with the ER stressor thapsigargin and the mitochondrial Hsp90 inhibitor gamitrinib augmented interorganelle stress signaling by elevating CHOP expression, and showed synergistic cytotoxic activity exclusively in cancer cells in vitro and in vivo.Conclusions: Collectively, mitochondrial Hsp90s confer cell death resistance to cancer cells by suppressing the mitochondria-initiated calcium-mediated interorganelle stress response.open0

Combined Dust Detection Algorithm by Using MODIS Infrared Channels over East Asia

A new dust detection algorithm is developed by combining the results of multiple dust detectionmethods using IR channels onboard the MODerate resolution Imaging Spectroradiometer (MODIS). Brightness Temperature Difference (BTD) between two wavelength channels has been used widely in previous dust detection methods. However, BTDmethods have limitations in identifying the offset values of the BTDto discriminate clear-sky areas. The current algorithm overcomes the disadvantages of previous dust detection methods by considering the Brightness Temperature Ratio (BTR) values of the dual wavelength channels with 30-day composite, the optical properties of the dust particles, the variability of surface properties, and the cloud contamination. Therefore, the current algorithm shows improvements in detecting the dust loaded region over land during daytime. Finally, the confidence index of the current dust algorithm is shown in 10 10 pixels of the MODIS observations. From January to June, 2006, the results of the current algorithm are within 64 to 81% of those found using the fine mode fraction (FMF) and aerosol index (AI) from the MODIS and Ozone Monitoring Instrument (OMI). The agreement between the results of the current algorithm and the OMI AI over the non-polluted land also ranges from 60 to 67% to avoid errors due to the anthropogenic aerosol. In addition, the developed algorithm shows statistically significant results at four AErosol RObotic NETwork (AERONET) sites in East Asia

Improvement of Aerosol Optical Depth Retrieval over Hong Kong from a Geostationary Meteorological Satellite Using Critical Reflectance with Background Optical Depth Correction

Despite continuous efforts to retrieve aerosol optical depth (AOD) using a conventional 5-channelmeteorological imager in geostationary orbit, the accuracy in urban areas has been poorer than other areas primarily due to complex urban surface properties and mixed aerosol types from different emission sources. The two largest error sources in aerosol retrieval have been aerosol type selection and surface reflectance. In selecting the aerosol type from a single visible channel, the season-dependent aerosol optical properties were adopted from longterm measurements of Aerosol Robotic Network (AERONET) sun-photometers. With the aerosol optical properties obtained fromthe AERONET inversion data, look-up tableswere calculated by using a radiative transfer code: the Second Simulation of the Satellite Signal in the Solar Spectrum (6S). Surface reflectance was estimated using the clear sky composite method, awidely used technique for geostationary retrievals. Over East Asia, the AOD retrieved from the Meteorological Imager showed good agreement, although the values were affected by cloud contamination errors. However, the conventional retrieval of the AOD over Hong Kong was largely underestimated due to the lack of information on the aerosol type and surface properties. To detect spatial and temporal variation of aerosol type over the area, the critical reflectance method, a technique to retrieve single scattering albedo (SSA), was applied. Additionally, the background aerosol effect was corrected to improve the accuracy of the surface reflectance over Hong Kong. The AOD retrieved froma modified algorithmwas compared to the collocated data measured by AERONET in Hong Kong. The comparison showed that the new aerosol type selection using the critical reflectance and the corrected surface reflectance significantly improved the accuracy of AODs in Hong Kong areas,with a correlation coefficient increase from0.65 to 0.76 and a regression line change from MI [basic algorithm] = 0.41AERONET + 0.16 to MI [new algorithm] = 0.70AERONET + 0.01

GOCI Yonsei Aerosol Retrieval (YAER) algorithm and validation during the DRAGON-NE Asia 2012 campaign

The Geostationary Ocean Color Imager (GOCI) onboard the Communication, Ocean, and Meteorological Satellite (COMS) is the first multi-channel ocean color imager in geostationary orbit. Hourly GOCI top-of-atmosphere radiance has been available for the retrieval of aerosol optical properties over East Asia since March 2011. This study presents improvements made to the GOCI Yonsei Aerosol Retrieval (YAER) algorithm together with validation results during the Distributed Regional Aerosol Gridded Observation Networks - Northeast Asia 2012 campaign (DRAGON-NE Asia 2012 campaign). The evaluation during the spring season over East Asia is important because of high aerosol concentrations and diverse types of Asian dust and haze. Optical properties of aerosol are retrieved from the GOCI YAER algorithm including aerosol optical depth (AOD) at 550 nm, fine-mode fraction (FMF) at 550 nm, single-scattering albedo (SSA) at 440 nm, Angstrom exponent (AE) between 440 and 860 nm, and aerosol type. The aerosol models are created based on a global analysis of the Aerosol Robotic Networks (AERONET) inversion data, and covers a broad range of size distribution and absorptivity, including nonspherical dust properties. The Cox-Munk ocean bidirectional reflectance distribution function (BRDF) model is used over ocean, and an improved minimum reflectance technique is used over land. Because turbid water is persistent over the Yellow Sea, the land algorithm is used for such cases. The aerosol products are evaluated against AERONET observations and MODIS Collection 6 aerosol products retrieved from Dark Target (DT) and Deep Blue (DB) algorithms during the DRAGON-NE Asia 2012 campaign conducted from March to May 2012. Comparison of AOD from GOCI and AERONET resulted in a Pearson correlation coefficient of 0.881 and a linear regression equation with GOCI AOD = 1.083 x AERONET AOD -0.042. The correlation between GOCI and MODIS AODs is higher over ocean than land. GOCI AOD shows better agreement with MODIS DB than MODIS DT. The other GOCI YAER products (AE, FMF, and SSA) show lower correlation with AERONET than AOD, but still show some skills for qualitative use.open1

Combination treatment with doxorubicin and gamitrinib synergistically augments anticancer activity through enhanced activation of Bim

Background: A common approach to cancer therapy in clinical practice is the combination of several drugs to boost the anticancer activity of available drugs while suppressing their unwanted side effects. In this regard, we examined the efficacy of combination treatment with the widely-used genotoxic drug doxorubicin and the mitochondriotoxic Hsp90 inhibitor gamitrinib to exploit disparate stress signaling pathways for cancer therapy.Methods: The cytotoxicity of the drugs as single agents or in combination against several cancer cell types was analyzed by MTT assay and the synergism of the drug combination was evaluated by calculating the combination index. To understand the molecular mechanism of the drug synergism, stress signaling pathways were analyzed after drug combination. Two xenograft models with breast and prostate cancer cells were used to evaluate anticancer activity of the drug combination in vivo. Cardiotoxicity was assessed by tissue histology and serum creatine phosphokinase concentration.Results: Gamitrinib sensitized various human cancer cells to doxorubicin treatment, and combination treatment with the two drugs synergistically increased apoptosis. The cytotoxicity of the drug combination involved activation and mitochondrial accumulation of the proapoptotic Bcl-2 family member Bim. Activation of Bim was associated with increased expression of the proapoptotic transcription factor C/EBP-homologous protein and enhanced activation of the stress kinase c-Jun N-terminal kinase. Combined drug treatment with doxorubicin and gamitrinib dramatically reduced in vivo tumor growth in prostate and breast xenograft models without increasing cardiotoxicity.Conclusions: The drug combination showed synergistic anticancer activities toward various cancer cells without aggravating the cardiotoxic side effects of doxorubicin, suggesting that the full therapeutic potential of doxorubicin can be unleashed through combination with gamitrinib.open

Development of a Mitochondria-Targeted Hsp90 Inhibitor Based on the Crystal Structures of Human TRAP1

The mitochondrial pool of Hsp90 and its mitochondrial paralogue, TRAP1, suppresses cell death and reprograms energy metabolism in cancer cells; therefore, Hsp90 and TRAP1 have been suggested as target proteins for anticancer drug development. Here, we report that the actual target protein in cancer cell mitochondria is TRAP1, and current Hsp90 inhibitors cannot effectively inactivate TRAP1 because of their insufficient accumulation in the mitochondria. To develop mitochondrial TRAP1 inhibitors, we determined the crystal structures of human TRAP1 complexed with Hsp90 inhibitors. The isopropyl amine of the Hsp90 inhibitor PU-H71 was replaced with the mitochondria-targeting moiety triphenylphosphonium to produce SMTIN-P01. SMTIN-P01 showed a different mode of action from the nontargeted PU-H71, as well as much improved cytotoxicity to cancer cells. In addition, we determined the structure of a TRAP1-adenylyl-imidodiphosphate (AMP-PNP) complex. On the basis of comparative analysis of TRAP1 structures, we propose a molecular mechanism of ATP hydrolysis that is crucial for chaperone function. ??? 2015 American Chemical Societyclose0