Lens Epithelium-Derived Growth Factor Is an Hsp70-2 Regulated Guardian of Lysosomal Stability in Human Cancer

Daugaard, Mads; Kirkegaard‐Sørensen, Thomas; Ostenfeld, Marie Stampe; Aaboe, Mads; Høyer-Hansen, Maria; Ørntoft, Torben F.; Rohde, Mikkel; Jäättelä, Marja

doi:10.1158/0008-5472.can-06-4121

Cited by 119 publications

(137 citation statements)

References 46 publications

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“…Finally, following the protein elution by 2-ME, isotope-coded affinity tag or thiolbased tandem mass tag labels could be used for a more accurate quantification of only the thiol-containing peptides, allowing the identification of specific reduction sites and the quantification of their enrichment using nTrx1 C35S . PSIP1/LEDGF is a stress-regulated protein reported to be important for cell survival (45) and implicated as having oncogenic properties (46). It is also known as Dense Fine Speckles 70-kDa protein (DFS 70) or transcriptional coactivator p75/p52 and is a transcriptional co-activator and a host factor that assists HIV integration (47,48).…”

Section: Discussionmentioning

confidence: 99%

Identification of Novel Nuclear Targets of Human Thioredoxin 1

Jain

et al. 2014

Molecular & Cellular Proteomics

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The dysregulation of protein oxidative post-translational modifications has been implicated in stress-related diseases. Trx1 is a key reductase that reduces specific disulfide bonds and other cysteine post-translational modifications. Although commonly in the cytoplasm, Trx1 can also modulate transcription in the nucleus. However, few Trx1 nuclear targets have been identified because of the low Trx1 abundance in the nucleus. Here, we report the large-scale proteomics identification of nuclear Trx1 targets in human neuroblastoma cells using an affinity capture strategy wherein a Trx1C35S mutant is expressed. The wild-type Trx1 contains a conserved C32XXC35 motif, and the C32 thiol initiates the reduction of a target disulfide bond by forming an intermolecular disulfide with one of the oxidized target cysteines, resulting in a transient Trx1-target protein complex. The reduction is rapidly consummated by the donation of a C35 proton to the target molecule, forming a Trx1 C32-C35 disulfide, and results in the concurrent release of the target protein containing reduced thiols. By introducing a point mutation (C35 to S35) in Trx1, we ablated the rapid dissociation of Trx1 from its reduction targets, thereby allowing the identification of 45 putative nuclear Trx1 targets. Unexpectedly, we found that PSIP1, also known as LEDGF, was sensitive to both oxidation and Trx1 reduction at Cys 204. LEDGF is a transcription activator that is vital for regulating cell survival during HIV-1 infection. Overall, this study suggests that Trx1 may play a broader role than previously believed that might include regulating transcription, RNA processing, and nuclear pore function in human cells. Molecular

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Section: Discussionmentioning

confidence: 99%

Identification of Novel Nuclear Targets of Human Thioredoxin 1

Jain

et al. 2014

Molecular & Cellular Proteomics

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“…Under MHT without cell death, early induction of HSPs may exert central cytoprotective effects that prevent cell death (10)(11)(12). HSPs including DNAJA1 (29), DNAJB1 (30) and HSPA1B (31), and BAG3 (32) have been previously described as anti-cell-death molecules. A previous report indicated that the specific protein interaction between BAG3 and Hsp70 occurred and that silencing of BAG3 attenuated apoptosis in the colonic cancer cell line RKO (32).…”

Section: Discussionmentioning

confidence: 99%

Gene networks related to the cell death elicited by hyperthermia in human oral squamous cell carcinoma HSC-3 cells

Tabuchi

Wada

Furusawa³

et al. 2011

Int J Mol Med

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Abstract. Local hyperthermia (HT) for various types of malignant tumors has shown promising antitumor effects. To confirm the detailed molecular mechanism underlying cell death induced by HT, gene expression patterns and gene networks in human oral squamous cell carcinoma (OSCC) cells were examined using a combination of DNA microarray and bioinformatics tools. OSCC HSC-3 cells were treated with HT at 44˚C for 90 min or mild hyperthermia (MHT) at 42˚C for 90 min, followed by culturing at 37˚C for 0-24 h. Treatment of cells with HT prevented cell proliferation (62%) and induced cell death (17%), whereas these alterations were not observed in cells treated with MHT. Microarray analysis revealed substantial differences with respect to gene expression patterns and biological function for the two different hyperthermic treatments. Moreover, we identified the temperature-specific gene networks D and H that were obtained from significantly up-regulated genes in the HT and MHT conditions, respectively, using Ingenuity pathway analysis tools. Gene network D, which contains 14 genes such as ATF3, DUSP1 and JUN, was associated with relevant biological functions including cell death and cellular movement. Gene network H, which contains 13 genes such as BAG3, DNAJB1 and HSPA1B, was associated with cellular function and maintenance and cellular assembly and organization. These findings provide a basis for understanding the detailed molecular mechanisms of cell death elicited by HT in human OSCC cells. IntroductionIn the treatment of oral squamous cell carcinoma (OSCC), treatment outcomes have improved in the past two decades due to progress in reconstructive techniques, stereotactic radiotherapy, new anticancer drugs such as taxanes, and combinations of these therapeutic modalities (1). Nonetheless, it is well known that patients with advanced tumors or tumor recurrence have a poor prognosis with a median survival period less than one year (2). Local hyperthermia (HT) for various malignant tumors including OSCC has been recognized as an effective and attractive tool with the advantages of relatively few side effects and slight damage to normal tissue. Combinations of HT with chemotherapy, radiotherapy or both have been clinically used for patients with cancer in various organs, and their antitumor effects have been verified by many clinical trials (3-7).In general, HT elicits a wide spectrum of stress responses such as induction of heat shock proteins (HSPs), protein aggregation, an imbalance of protein homeostasis, DNA and RNA damage, reactive oxygen species production, cell growth arrest and cell death in mammalian cells (8,9). In particular, HSPs, which are induced by heat, behave as molecular chaperones and exert strong cytoprotective effects that prevent cell death. The treatment of cells with HT induces numerous signal transduction pathways which contribute variously to cell death and survival (10-12). Although many biological processes are affected by HT, the overall responses to HT in mammalian cells remain unknown.Re...

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“…In addition, Hsp70 depletion mediated by antisense constructs or small interfering RNAs induces caspase-independent cell death of cancer cells but not of non-tumorigenic cells (Nylandsted et al, 2000). The specific depletion of one protein of the Hsp70 family, Hsp70-2, triggers LMPand cathepsin-dependent cell death (Daugaard et al, 2007a). This pathway seems to be mediated by the lens epithelium-derived growth factor, which is a transcriptional co-activator that regulates the transcription of several stress genes including Hsp70-2 and that confers protection against several proapoptotic stimuli (Ganapathy et al, 2003).…”

Section: Endogenous Inhibitors Of Lysosome-mediated Cell Deathmentioning

confidence: 99%

Lysosomal membrane permeabilization in cell death

2008

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Mitochondrial outer membrane permeabilization (MOMP) constitutes one of the major checkpoint(s) of apoptotic and necrotic cell death. Recently, the permeabilization of yet another organelle, the lysosome, has been shown to initiate a cell death pathway, in specific circumstances. Lysosomal membrane permeabilization (LMP) causes the release of cathepsins and other hydrolases from the lysosomal lumen to the cytosol. LMP is induced by a plethora of distinct stimuli including reactive oxygen species, lysosomotropic compounds with detergent activity, as well as some endogenous cell death effectors such as Bax. LMP is a potentially lethal event because the ectopic presence of lysosomal proteases in the cytosol causes digestion of vital proteins and the activation of additional hydrolases including caspases. This latter process is usually mediated indirectly, through a cascade in which LMP causes the proteolytic activation of Bid (which is cleaved by the two lysosomal cathepsins B and D), which then induces MOMP, resulting in cytochrome c release and apoptosome-dependent caspase activation. However, massive LMP often results in cell death without caspase activation; this cell death may adopt a subapoptotic or necrotic appearance. The regulation of LMP is perturbed in cancer cells, suggesting that specific strategies for LMP induction might lead to novel therapeutic avenues.

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Lens Epithelium-Derived Growth Factor Is an Hsp70-2 Regulated Guardian of Lysosomal Stability in Human Cancer

Cited by 119 publications

References 46 publications

Identification of Novel Nuclear Targets of Human Thioredoxin 1

Identification of Novel Nuclear Targets of Human Thioredoxin 1

Gene networks related to the cell death elicited by hyperthermia in human oral squamous cell carcinoma HSC-3 cells

Lysosomal membrane permeabilization in cell death

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