Thapsigargin mechanism of action

Federal government websites often end in. The site is secure. A sesquiterpene lactone, thapsigargin, is a phytochemical found in the roots and fruits of Mediterranean plants from Thapsia L. This biological activity encouraged studies on the use of thapsigargin as a novel antineoplastic agent, which were, thapsigargin mechanism of action, however, hampered due to high toxicity of this compound to normal cells.

Thapsigargin raises cytosolic intracellular calcium concentration by blocking the ability of the cell to pump calcium into the sarcoplasmic and endoplasmic reticula. Store-depletion can secondarily activate plasma membrane calcium channels , allowing an influx of calcium into the cytosol. Depletion of ER calcium stores leads to ER stress and activation of the unfolded protein response. Thapsigargin treatment and the resulting ER calcium depletion inhibits autophagy independent of the UPR. Thapsigargin is useful in experimentation examining the impacts of increasing cytosolic calcium concentrations and ER calcium depletion.

Thapsigargin mechanism of action

Federal government websites often end in. The site is secure. Box Blindern, Oslo, Norway,. However, the exact mechanisms whereby SERCA inhibition induces cell death are incompletely understood. Here, we report that low 0. Furthermore, caspase activation and cell death were associated with a sustained unfolded protein response. Experimentally, specific effects of blocking SERCA activity can be conveniently studied with the aid of thapsigargin Tg , a sesquiterpene lactone, the structure of which is shown in Fig. Interestingly, chemically modified analogs of Tg 12 are being used for antineoplastic purposes despite the general cellular toxicity of these compounds against both cancer and normal cells. The problem of toxicity in a therapeutic setting has been addressed by producing inactive prodrugs that can be activated by proteases to target specific cancer types 12 , With respect to prostate cancer, strategies have been designed to produce prodrugs that are transformed into active antineoplastic analogs upon proteolytic cleavage by prostate-specific antigen PSA 14 , This entails substituting the butanoate at O-8 in Tg Fig. In vivo administration of this prodrug leads to extracellular formation of the lipophilic and cytotoxic Tg analog Leu-8ADT Fig.

Download as PDF Printable version. Endoplasmic-reticulum calcium depletion and disease.

Cell Communication and Signaling volume 18 , Article number: 12 Cite this article. Metrics details. Cell death triggered by unmitigated endoplasmic reticulum ER stress plays an important role in physiology and disease, but the death-inducing signaling mechanisms are incompletely understood. To gain more insight into these mechanisms, the ER stressor thapsigargin Tg is an instrumental experimental tool. Additionally, Tg forms the basis for analog prodrugs designed for cell killing in targeted cancer therapy.

Thapsigargin, the first representative of the hexaoxygenated guaianolides, was isolated 40 years ago in order to understand the skin-irritant principles of the resin of the umbelliferous plant Thapsia garganica. Thapsigargin has become a tool for investigation of the importance of SERCA in intracellular calcium homeostasis. In addition, complex formation of thapsigargin with SERCA has enabled crystallization and structure determination of calcium-free states by X-ray crystallography. Development of protocols for selective transformation of thapsigargin disclosed the chemistry and facilitated total synthesis of the molecule. Conversion of trilobolide into thapsigargin offered an economically feasible sustainable source of thapsigargin, which enables a future drug production.

Thapsigargin mechanism of action

Thapsigargin raises cytosolic intracellular calcium concentration by blocking the ability of the cell to pump calcium into the sarcoplasmic and endoplasmic reticula. Store-depletion can secondarily activate plasma membrane calcium channels , allowing an influx of calcium into the cytosol. Depletion of ER calcium stores leads to ER stress and activation of the unfolded protein response. Thapsigargin treatment and the resulting ER calcium depletion inhibits autophagy independent of the UPR. Thapsigargin is useful in experimentation examining the impacts of increasing cytosolic calcium concentrations and ER calcium depletion. A study from the University of Nottingham showed promising results for its use against Covid and other coronavirus. The complete biosynthesis of thapsigargin has yet to be elucidated. A proposed biosynthesis starts with the farnesyl pyrophosphate. The first step is controlled by the enzyme germacrene B synthase.

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Iurlaro R, Munoz-Pinedo C. Andrews and Jarkko Ylanko for assistance to postdoctoral fellow Pankaj Sehgal, the use of the laboratory to perform many of the cell biological experiments, and inspiring discussions on all aspects of the present work. If we can understand the molecular mechanisms that initiate cell death under such conditions, it can lay the ground for the development of novel treatment modalities for various diseases. This article contains supplemental Figs. To overcome this limitation and direct the cytotoxicity of Tg towards cancer cells, sparing normal tissue, the Tg-based pro-drug strategy has been developed [ 1 , 14 , 55 , 56 , 57 , 58 ]. Note that, under these conditions in the presence of excess molar EpoTg, activities could be measured without recognizable error by direct addition to the enzymatic assay buffer. J Biol Chem. Mol Cell Biol. CHOP is involved in endoplasmic reticulum stress-induced apoptosis by enhancing DR5 expression in human carcinoma cells. Autophagosomal membranes can act as signaling platforms for oligomerization and activation of caspase-8 in response to treatment with proteasome- or sphingosine kinase inhibitors [ 63 , 64 , 65 ]. You can also search for this author in PubMed Google Scholar. Proteasome inhibition can induce an autophagy-dependent apical activation of caspase

Thapsigargin, the first representative of the hexaoxygenated guaianolides, was isolated 40 years ago in order to understand the skin-irritant principles of the resin of the umbelliferous plant Thapsia garganica. Thapsigargin has become a tool for investigation of the importance of SERCA in intracellular calcium homeostasis. In addition, complex formation of thapsigargin with SERCA has enabled crystallization and structure determination of calcium-free states by X-ray crystallography.

Immediately after addition of MgATP, 0. Jeffrey M. The molecular mechanisms responsible for JNK activation in the first versus the second phase may be different. Skip to main content. Molecular requirements for cell death induction by therapy-relevant Tg analogs were identical to those observed with Tg. Brown et al. Acknowledgments We are grateful to Prof. Cancer Cell. David W. Confirming a critical role for death receptor 5 and caspase-8 in apoptosis induction by endoplasmic reticulum stress. Prostate-specific antigen-activated thapsigargin prodrug as targeted therapy for prostate cancer. Jesper V. For analysis, cell masks were set using the Incucyte ZOOM software and following the recommendations from the provider. Moreover, it will be important to decipher the roles of the various UPR arms and downstream factors in Tg-induced cell death. Cell death induced by the ER stressor thapsigargin involves death receptor 5, a non-autophagic function of MAP1LC3B, and distinct contributions from unfolded protein response components.