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Endoplasmic reticulum stress leads to lipid accumulation through upregulation of SREBP-1c in normal hepatic and hepatoma cells.

Endoplasmic reticulum stress (ERS) has been found in non-alcoholic fatty liver disease. The study was to further explore the mechanistic relationship between ERS and lipid accumulation. To induce ERS, the hepatoblastoma cell line HepG2 and the normal human L02 cell line were exposed to Tg for 48 h. RT-PCR and Western blot were performed to evaluate glucose-regulated protein (GRP-78) expression as a marker of ERS. ER ultrastructure was assessed by electron microscopy. Triglyceride content was examined by Oil Red O staining and quantitative intracellular triglyceride assay. The hepatic nuclear s

Protein synthesis in plasma cells is regulated by crosstalk between endoplasmic reticulum stress and mTOR signaling.

Plasma cells (PCs) secrete copious levels of immunoglobulins. To achieve this, their endoplasmic reticulum (ER) undergoes expansion in a process that requires continuous ER stress and activation of the unfolded protein response. It is important that protein synthesis, the driver of ER stress, is regulated in a manner that does not induce apoptosis. We followed protein synthesis in murine splenic B cells activated in vitro with LPS. Total protein synthesis levels increased and then steeply decreased when the cells acquired a secretory phenotype. We explored the involvement of two mechanisms in

Ca2+-dependent regulation of rho GTPases triggers turning of nerve growth cones.

Cytoplasmic Ca2+ elevation and changes in Rho GTPase activity are both known to mediate axon guidance by extracellular factors, but the causal relationship between these two events has been unclear. Here we show that direct elevation of cytoplasmic Ca2+ by extracellular application of a low concentration of ryanodine, which activated Ca2+ release from intracellular stores, upregulated Cdc42/Rac, but downregulated RhoA, in cultured cerebellar granule cells and human embryonic kidney 293T cells. Chemoattractive turning of the growth cone triggered by a gradient of ryanodine was blocked by overex

Induction of store-operated calcium entry (SOCE) suppresses glioblastoma growth by inhibiting the Hippo pathway transcriptional coactivators YAP/TAZ.

Glioblastomas (GBM) are the most aggressive brain cancers without effective therapeutics. The Hippo pathway transcriptional coactivators YAP/TAZ were implicated as drivers in GBM progression and could be therapeutic targets. Here we found in an unbiased screen of 1650 compounds that amlodipine is able to inhibit survival of GBM cells by suppressing YAP/TAZ activities. Instead of its known function as an L-type calcium channel blocker, we found that amlodipine is able to activate Ca2+ entry by enhancing store-operated Ca2+ entry (SOCE). Amlodipine as well as approaches that cause store depletio

Transient oxidative stress evokes early changes in the functional properties of neonatal rat hypoglossal motoneurons in vitro.

Oxidative stress of motoneurons is believed to be an important contributor to neurodegeneration underlying the familial (and perhaps even the sporadic) form of amyotrophic lateral sclerosis (ALS). This concept has generated numerous rodent genetic models with inborn oxidative stress to mimic the clinical condition. ALS is, however, a predominantly sporadic disorder probably triggered by environmental causes. Thus, it is interesting to understand how wild-type motoneurons react to strong oxidative stress as this response might cast light on the presymptomatic disease stage. The present study us

Serum and glucocorticoid-regulated kinase 1 (SGK1) activation in breast cancer: requirement for mTORC1 activity associates with ER-alpha expression.

Mammalian target of rapamycin (mTOR) is an attractive target for cancer treatment. While rapamycin and its derivatives (e.g., everolimus) have been shown to inhibit mTOR signaling and cell proliferation in preclinical models of breast cancer, mTOR inhibition has demonstrated variable clinical efficacy with a trend toward better responses in estrogen receptor alpha positive (ERα+) compared to ERα negative (ERα-) tumors. Recently, serum- and glucocorticoid-regulated kinase 1 (SGK1) was identified as a substrate of mTOR kinase activity. Previous studies have alternatively suggested that either mT

miR-30d, miR-181a and miR-199a-5p cooperatively suppress the endoplasmic reticulum chaperone and signaling regulator GRP78 in cancer.

GRP78, a major endoplasmic reticulum chaperone and signaling regulator, is commonly overexpressed in cancer. Moreover, induction of GRP78 by a variety of anti-cancer drugs, including histone deacetylase inhibitors, confers chemoresistance to cancer, thereby contributing to tumorigenesis. Thus, therapies aimed at decreasing GRP78 levels, which results in the inhibition of tumor cell proliferation and resensitization of tumor cells to chemotherapeutic drugs may hold promise for cancer treatment. Despite advances in our understanding of GRP78 actions, little is known about endogenous inhibitors c

Carfilzomib enhances cisplatin-induced apoptosis in SK-N-BE(2)-M17 human neuroblastoma cells.

Neuroblastoma is a solid malignant tumor of the sympathetic nervous system, which accounts for 8-10% of childhood cancers. Considering the overall high risk and poor prognosis associated with neuroblastoma, effective therapeutics should be developed to improve patient survival and quality of life. A recent study showed that a proteasome inhibitor, carfilzomib (CFZ), reduced cell viability of SK-N-BE(2)-M17 neuroblastoma cells. Therefore, we investigated the molecular mechanisms by which CFZ lower the cell viability of neuroblastoma cells. CFZ reduced cell viability via cell cycle arrest at G2/

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… The level of P-eIF2α induced by CFZ was comparable to that induced by thapsigargin (TG), a representative ER stress inducer. Although the dose- and time-dependent expression patterns were slightly different, most ER stress-associated protein levels increased in CFZ-treated cells. … Dimethyl sulfoxide (DMSO), N-acetyl-l-cysteine (NAC), propidium iodide (PI), DNase free-RNase A, 2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA), 3,3′-dihexyloxacarbocyanine iodide (DiOC6), Cis, thapsigargin (TG), and antibodies specific for β-actin were purchased from Sigma-Aldrich (St. …

Glutamate stimulates oligodendrocyte progenitor migration mediated via an alphav integrin/myelin proteolipid protein complex.

In the mammalian CNS, oligodendrocyte precursor cells (OPCs) express most neurotransmitter receptors, but their function remains unclear. The current studies suggest a physiological role for glutamate (AMPA and/or kainate) receptors in OPC migration. AMPA stimulated alphav integrin-mediated OPC migration by increasing both the rate of cell movement and the frequency of Ca2+ transients. A protein complex containing the myelin proteolipid protein (PLP) and alphav integrin modulated the AMPA-stimulated migration, and stimulation of OPC AMPA receptors resulted in increased association of the AMPA

Targeting Autophagy with Natural Products as a Potential Therapeutic Approach for Cancer.

Macro-autophagy (autophagy) is a highly conserved eukaryotic intracellular process of self-digestion caused by lysosomes on demand, which is upregulated as a survival strategy upon exposure to various stressors, such as metabolic insults, cytotoxic drugs, and alcohol abuse. Paradoxically, autophagy dysfunction also contributes to cancer and aging. It is well known that regulating autophagy by targeting specific regulatory molecules in its machinery can modulate multiple disease processes. Therefore, autophagy represents a significant pharmacological target for drug development and therapeutic

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… pathway | - | KRAS mutant CRC cells | Rho kinase inhibitor [ 121 , 145 , 146 ] Initiation | (–)-Guaiol | | Sesquiterpene alcohol | Guaiacum officinale Guaiacum sanctum | Inhibition of the mTOR pathway | Antibacterial activity Gout | NSCLC cells | Blocking of mTORC2-AKT signaling [ 147 ] Initiation | Thapsigargin …

Pterostilbene in the Management and Treatment of Multiple Myeloma.

Multiple Myeloma is a malignancy of the plasma cells of the bone marrow. This cancer rapidly becomes refractory to many of the currently available chemotherapeutic regimens used against it, requiring an alternative option or supplementary therapy. Pterostilbene is a naturally occurring compound in a variety of commonly consumed plants that exhibits strong antioxidant properties and, lately, has shown increasing activity as an anti-neoplastic compound. A review of the literature published since 2015 on Google Scholar and PubMed was conducted, with a focus on randomized controlled trials and an

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… Finally, when co-administered with another naturally occurring and plant-derived compound, Thapsigargin, PT was able to significantly decrease viability of esophageal cancer cells via increased ERS levels [ 21 ]. …

Calcium Signalling in Breast Cancer Associated Bone Pain.

Calcium (Ca2+) is involved as a signalling mediator in a broad variety of physiological processes. Some of the fastest responses in human body like neuronal action potential firing, to the slowest gene transcriptional regulation processes are controlled by pathways involving calcium signalling. Under pathological conditions these mechanisms are also involved in tumoral cells reprogramming, resulting in the altered expression of genes associated with cell proliferation, metastatisation and homing to the secondary metastatic site. On the other hand, calcium exerts a central function in nocicepti

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… Again, Orai3 overexpression, protects T47D cells against cell death inducers like cisplatin, fluorouracil, paclitaxel, staurosporin and thapsigargin, suggesting a role for Orai3 in breast cancer resistance to chemotherapeutics [ 43 ]. … Inhibition of the sarco/endoplasmic reticulum (ER) Ca2+-ATPase by thapsigargin analogs induces cell death via ER Ca2+ depletion and the unfolded protein response. J. Biol. Chem. 2017;292:19656–19673. doi: 10.1074/jbc.M117.796920. 56. …

Proceedings of International Conference on Cell Death in Cancer and Toxicology. February 20-22, 2018. Guest Editors: Kausar M. Ansari, CSIR-IITR, India and Dhyan Chandra, Roswell Park, USA.

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… Our findings suggest that apicidin and thapsigargin target different OXPHOS complexes, we further investigated the effect of thapsigargin or apicidin on functional significance of cytokines in mitochondrial function and apoptotic cell death. … Significantly elevated caspase‐3 was observed upon combined exposure of apicidin and thapsigargin with altered IL‐8 expression and release. …

Cataract Induced by Glucocorticoids.

Glucocorticoids (GCs) remain a cornerstone therapy for noninfectious uveitis and autoimmune disorders; however, chronic administration is strongly associated with sight-threatening complications, particularly glucocorticoid-induced cataracts (GIC). This comprehensive review synthesizes current evidence on the molecular pathogenesis, epidemiological patterns, and clinical management of GIC. Epidemiological analyses indicate that over 50% of patients receiving systemic corticosteroids for >60 days develop ocular complications, with cataract formation (36%) and glaucoma (16%) representing the pre

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… translocation of EMT transcription factors, driving spindle-shaped morphological transition and invasive LEC migration. 12 Complementing this mechanism, endoplasmic reticulum (ER) stress activates unfolded protein response (UPR) sensors (GRP78, ATF6, IRE1α) in human LECs (HLECs), as evidenced by tunicamycin/thapsigargin …

ER-mitochondria tethering and its signaling: A novel therapeutic target in breast cancer.

Communication between the endoplasmic reticulum (ER) and mitochondria through mitochondria-associated ER membranes (MAMs) is assisted by tethering proteins and signaling pathways, manifesting the dynamic exchange of lipids, calcium, and signaling molecules. However, dysregulation of tethering and signaling proteins contributes to the progression of breast cancer (BC). Abnormal MAM structures and altered ER-mitochondrial tethering impair mitochondrial functions and thereby drive BC progression. Altered mitochondrial dynamics, often characterized by dysregulated dynamin-related protein 1 (Drp1)

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… Thapsigargin targets the Sarco/ER Ca2+-ATPase (SERCA) pump and depletes calcium stores, resulting in the elevation of the misfolded proteins and activating UPR, which, in turn, causes ER stress. … 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. Cell Commun. Signal. 2020;18:12. doi: 10.1186/s12964-019-0499-z. 138. …

Research advances in peptide‒drug conjugates.

Peptide‒drug conjugates (PDCs) are drug delivery systems consisting of a drug covalently coupled to a multifunctional peptide via a cleavable linker. As an emerging prodrug strategy, PDCs not only preserve the function and bioactivity of the peptides but also release the drugs responsively with the cleavable property of the linkers. Given the ability to significantly improve the circulation stability and targeting of drugs in vivo and reduce the toxic side effects of drugs, PDCs have already been extensively applied in drug delivery. Herein, we review the types and mechanisms of peptides, link

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… Phase I/II Bicycle Therapeutics BTP-277 Endocrine cancer and small cell lung cancer fCYwKTC C (2,7 SS) Disulfide DM-1 Microtubule destabilizers (Tubulin polymerization inhibitors) and somatostatin receptor type 2 (SSTR2) ligands Phase I/II Tarveda Therapeutics G-202 Solid tumors D γ E γ E γ E γ E Amide Thapsigargin … Therapeutics BTP-277 | Endocrine cancer and small cell lung cancer | fCYwKTC C (2,7 SS) | Disulfide | DM-1 | Microtubule destabilizers (Tubulin polymerization inhibitors) and somatostatin receptor type 2 (SSTR2) ligands | Phase I/II | Tarveda Therapeutics G-202 | Solid tumors | D γ E γ E γ E γ E | Amide | Thapsigargin …

Applied information retrieval and multidisciplinary research: new mechanistic hypotheses in complex regional pain syndrome.

BackgroundCollaborative efforts of physicians and basic scientists are often necessary in the investigation of complex disorders. Difficulties can arise, however, when large amounts of information need to reviewed. Advanced information retrieval can be beneficial in combining and reviewing data obtained from the various scientific fields. In this paper, a team of investigators with varying backgrounds has applied advanced information retrieval methods, in the form of text mining and entity relationship tools, to review the current literature, with the intention to generate new insights into th

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… Activation of p55 tumor necrosis factor-alpha receptor-1 coupled to tumor necrosis factor receptor-associated factor 2 stimulates intercellular adhesion molecule-1 expression by modulating a thapsigargin-sensitive pathway in human tracheal smooth muscle cells Mol Pharmacol 2000 58 237 245 10860946 10.1124 …

Direct Endoplasmic Reticulum Targeting by the Selective Alkylphospholipid Analog and Antitumor Ether Lipid Edelfosine as a Therapeutic Approach in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC), the most common malignancy of the pancreas, shows a dismal and grim overall prognosis and survival rate, which have remained virtually unchanged for over half a century. PDAC is the most lethal of all cancers, with the highest mortality-to-incidence ratio. PDAC responds poorly to current therapies and remains an incurable malignancy. Therefore, novel therapeutic targets and drugs are urgently needed for pancreatic cancer treatment. Selective induction of apoptosis in cancer cells is an appealing approach in cancer therapy. Apoptotic cell death is highly

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… Bortezomib promotes apoptosis triggered by classic ER stress inducers (such as tunicamycin—an inhibitor of protein glycosylation—and thapsigargin—an inhibitor of sarco/endoplasmic reticulum Ca 2+ -ATPases) via a c-Jun NH 2 -terminal kinase (JNK)-dependent mechanism [ 122 ]. … ER stress and its downstream cell death pathways can be engaged by a wide array of stimuli (e.g., thapsigargin, tunicamycin, brefeldin A, 2-deoxyglucose, chronic exposure to long-chain free fatty acids, cannabinoids, several plant-derived natural compounds) and anticancer drugs (e.g., bortezomib) in …

Ion Channels in Multiple Myeloma: Pathogenic Role and Therapeutic Perspectives.

Ion channels are pore-forming proteins that allow ions to flow across plasma membranes and intracellular organelles in both excitable and non-excitable cells. They are involved in the regulation of several biological processes (i.e., proliferation, cell volume and shape, differentiation, migration, and apoptosis). Recently, the aberrant expression of ion channels has emerged as an important step of malignant transformation, tumor progression, and drug resistance, leading to the idea of "onco-channelopathy". Here, we review the contribution of ion channels and transporters in multiple myeloma (

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… Accordingly, treatment of CD45 + MM cells with thapsigargin, an inhibitor of the sarco/endoplasmic reticulum Ca 2+ ATPase (SERCA), increases cytosolic levels of Ca 2+ and triggers apoptosis in VDAC1-expressing MM cells ( Figure 1 ) [ 75 ]. …