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

Unleashing the full potential of Hsp90 inhibitors as cancer therapeutics through simultaneous inactivation of Hsp90, Grp94, and TRAP1

Cancer therapeutics: Extending a drug's reach A new drug that blocks heat shock proteins (HSPs), helper proteins that are co-opted by cancer cells to promote tumor growth, shows promise for cancer treatment. Several drugs have targeted HSPs, since cancer cells are known to hijack these helper proteins to shield themselves from destruction by the body. However, the drugs have had limited success. Hye-Kyung Park and Byoung Heon Kang at Ulsan National Institutes of Science and Technology in South Korea and coworkers noticed that the drugs were not absorbed into mitochondria, a key cellular compartment, and HSPs in this compartment were therefore not being blocked. They identified a new HSP inhibitor that can reach every cellular compartment and inhibit all HSPs. Testing in mice showed that this inhibitor effectively triggered death of tumor cells, and therefore shows promise for anti-cancer therapy. The Hsp90 family proteins Hsp90, Grp94, and TRAP1 are present in the cell cytoplasm, endoplasmic reticulum, and mitochondria, respectively; all play important roles in tumorigenesis by regulating protein homeostasis in response to stress. Thus, simultaneous inhibition of all Hsp90 paralogs is a reasonable strategy for cancer therapy. However, since the existing pan-Hsp90 inhibitor does not accumulate in mitochondria, the potential anticancer activity of pan-Hsp90 inhibition has not yet been fully examined in vivo. Analysis of The Cancer Genome Atlas database revealed that all Hsp90 paralogs were upregulated in prostate cancer. Inactivation of all Hsp90 paralogs induced mitochondrial dysfunction, increased cytosolic calcium, and activated calcineurin. Active calcineurin blocked prosurvival heat shock responses upon Hsp90 inhibition by preventing nuclear translocation of HSF1. The purine scaffold derivative DN401 inhibited all Hsp90 paralogs simultaneously and showed stronger anticancer activity than other Hsp90 inhibitors. Pan-Hsp90 inhibition increased cytotoxicity and suppressed mechanisms that protect cancer cells, suggesting that it is a feasible strategy for the development of potent anticancer drugs. The mitochondria-permeable drug DN401 is a newly identified in vivo pan-Hsp90 inhibitor with potent anticancer activity

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Interobserver Reliability of Tongue Diagnosis Using Traditional Korean Medicine for Stroke Patients

Observation of the tongue, also known as tongue diagnosis, is an important procedure in diagnosis by inspection in Traditional Korean medicine (TKM). We investigated the reliability of TKM tongue diagnosis in stroke patients by evaluating interobserver reliability regarding tongue indicators as part of the project named the Fundamental Study for the Standardization and Objectification of Pattern Identification in TKM for Stroke (SOPI-Stroke). A total of 658 patients with stroke admitted to 9 oriental medical university hospitals participated. Each patient was independently seen by two experts from the same department for an examination of the status of the tongue. Interobserver agreement about subjects regarding pattern identification with the same opinion between the raters (n = 451) was generally high, ranging from “moderate” to “excellent”. Interobserver agreement was nearly perfect for certain signs of special tongue appearance (mirror, spotted, and bluish purple), poor for one of the tongue colors (pale) and moderate for others. Clinicians displayed measurable agreement regarding tongue indicators via both observation and pattern identification consistency. However, interobserver reliability regarding tongue color and fur quality was relatively low. Therefore, it is necessary to improve objectivity and reproducibility of tongue diagnosis through the development of detail-oriented criteria and enhanced training of clinicians

Analog Self-Interference Cancellation With Practical RF Components for Full-Duplex Radios

One of the main obstacles in full-duplex radios is analog-to-digital converter (ADC) saturation on a receiver due to the strong self-interference (SI). To solve this issue, researchers have proposed two different types of analog self-interference cancellation (SIC) methods—i) passive suppression and ii) regeneration-and-subtraction of SI. For the latter case, the tunable RF component, such as a multi-tap circuit, reproduces and subtracts the SI. The resolutions of such RF components constitute the key factor of the analog SIC. Indeed, they are directly related to how well the SI is imitated. Another major issue in analog SIC is the inaccurate estimation of the SI channel due to the nonlinear distortions, which mainly come from the power amplifier (PA). In this paper, we derive a closed-form expression for the SIC performance of the multi-tap circuit; we consider how the RF components must overcome such practical impairments as digitally-controlled attenuators, phase shifters, and PA. For a realistic performance analysis, we exploit the measured PA characteristics and carry out a 3D ray-tracing-based, system-level throughput analysis. Our results confirm that the non-idealities of the RF components significantly affect the analog SIC performance. We believe our study provides insight into the design of the practical full-duplex system

Biological Toxicity and Inflammatory Response of Semi-Single-Walled Carbon Nanotubes

The toxicological studies on carbon nanotubes (CNTs) have been urgently needed from the emerging diverse applications of CNTs. Physicochemical properties such as shape, diameter, conductance, surface charge and surface chemistry of CNTs gained during manufacturing processes play a key role in the toxicity. In this study, we separated the semi-conductive components of SWCNTs (semi-SWCNTs) and evaluated the toxicity on days 1, 7, 14 and 28 after intratracheal instillation in order to determine the role of conductance. Exposure to semi-SWCNTs significantly increased the growth of mice and significantly decreased the relative ratio of brain weight to body weight. Recruitment of monocytes into the bloodstream increased in a time-dependent manner, and significant hematological changes were observed 28 days after exposure. In the bronchoalveolar lavage (BAL) fluid, secretion of Th2-type cytokines, particularly IL-10, was more predominant than Th1-type cytokines, and expression of regulated on activation normal T cell expressed and secreted (RANTES), p53, transforming growth factor (TGF)-β, and inducible nitric oxide synthase (iNOS) increased in a time-dependent manner. Fibrotic histopathological changes peaked on day 7 and decreased 14 days after exposure. Expression of cyclooxygenase-2 (COX-2), mesothelin, and phosphorylated signal transducer and activator of transcription 3 (pSTAT3) also peaked on day 7, while that of TGF-β peaked on days 7 and 14. Secretion of histamine in BAL fluid decreased in a time-dependent manner. Consequently, we suggest that the brain is the target organ of semi-SWCNTs brought into the lung, and conductance as well as length may be critical factors affecting the intensity and duration of the inflammatory response following SWCNT exposure