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Targeting LIPA independent of its lipase activity is a therapeutic strategy in solid tumors via induction of endoplasmic reticulum stress

ABSTRACT: Targeting LIPA independent of its lipase activity is a therapeutic strategy in solid tumors via induction of endoplasmic reticulum stress

PROVIDER: PRJNA714060 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13952700.fastq.gz	Fastqsanger.gz
	SRR13952671.fastq.gz	Fastqsanger.gz
	SRR13952672.fastq.gz	Fastqsanger.gz
	SRR13952673.fastq.gz	Fastqsanger.gz
	SRR13952674.fastq.gz	Fastqsanger.gz

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Targeting LIPA independent of its lipase activity is a therapeutic strategy in solid tumors via induction of endoplasmic reticulum stress

Project description:Triple-negative breast cancer (TNBC) has a poor clinical outcome, due to a lack of actionable therapeutic targets. Herein we define lysosomal acid lipase A (LIPA) as a viable molecular target in TNBC and identify a stereospecific small molecule (ERX-41) that binds LIPA. ERX-41 induces endoplasmic reticulum (ER) stress resulting in cell death, and this effect is on target as evidenced by specific LIPA mutations providing resistance. Importantly, we demonstrate that ERX-41 activity is independent of LIPA lipase function but dependent on its ER localization. Mechanistically, ERX-41 binding of LIPA decreases expression of multiple ER-resident proteins involved in protein folding. This targeted vulnerability has a large therapeutic window, with no adverse effects either on normal mammary epithelial cells or in mice. Our study implicates a targeted strategy for solid tumors, including breast, brain, pancreatic and ovarian, whereby small, orally bioavailable molecules targeting LIPA block protein folding, induce ER stress and result in tumor cell death.

2022-03-18 | GSE168800 | GEO

Targeting LIPA Independent of its Lipase Activity is a Therapeutic Strategy in Solid Tumors via Induction of Endoplasmic Reticulum Stress

Project description:Triple negative breast cancers (TNBC) are associated with poor clinical outcomes due to a lack of targeted therapies. Here, we identified a small molecule ERX-41 with potent activity against TNBC cell lines, primary tumor explants and xenografts. ERX-41 induced endoplasmic reticulum (ER) stress and caused cell death. We identified lysosomal acid lipase A (LIPA) gene as the molecular target for ERX-41 and critical for ERX-41 to induce ER stress and cell death. Mechanistically, interaction of ERX-41 with LIPA alters expression of multiple ER-resident proteins involved in protein folding. Importantly, we defined that ER localization of LIPA but not its lipase function are necessary for ERX-41 activity in TNBC. Our study implicates a new targeted strategy for multiple solid tumors, including breast, brain, pancreatic and ovarian, whereby a small orally bioavailable molecule (ERX-41) targeting LIPA blocks protein folding, induces ER stress and causes cell death.

2022-03-21 | MSV000089091 | MassIVE

Whole genome expression profiling of rice leaves treated with Xanthomonas oryzae pv. oryzae secreted cell wall degrading lipase/esteraseA (LipA) at early time points, 30 min. and 120 min.

Project description:Treatment of rice tissues with purified preparations of a Xanthomonas oryzae pv. oryzae (Xoo) secreted plant cell wall degrading enzyme, Lipase/Esterase (LipA), elicits cell wall damage induced innate immune responses. LipA activity is required for induction of defense responses. In order to characterize the early events during elaboration of cell wall degrading enzyme, Lipase/Esterase (LipA) induced innate immune response in rice, we have performed global gene expression profiling of rice leaves treated with purified LipA at early time points, 30 minutes and 120min, after treatment. Whole genome transcriptional profiling was performed using Affymetrix Rice GeneChips Leaves of two weeks old green house grown susceptible rice cultivar (Taichung Native-1; TN-1) were infiltrated with either 30-40μl of purified Xoo Lipase/Esterase (LipA)(500μg/ml) or with buffer (10mM potassium phosphate buffer pH 6.0) alone (as described in Jha et al. 2007; MPMI vol 20, pp 31-40). The plants were shifted to a growth chamber (28oC; 80% relative humidity; 12/12h light/dark cycle) 48 hours before the treatment. 20-30 leaf pieces covering the infiltrated zone from each of the treatments were harvested 30 min. and 120 min. after infiltration. Total RNA isolated from the pooled samples was subjected for expression analysis using Affymetrix GeneChip System. The experiment was repeated with three different biological replicates using RNA isolated from three batches of rice leaves treated with the freshly purified Xoo Lipase/Esterase (LipA)and the buffer Gene Expression profiling of rice leaves undergoing an innate immune respone induced by LipA (Lipase/Esterase A) enzyme

2015-06-30 | E-GEOD-53940 | biostudies-arrayexpress

Whole genome expression profiling of rice leaves treated with Xanthomonas oryzae pv. oryzae secreted cell wall degrading lipase/esteraseA (LipA) at early time points, 30 min. and 120 min.

2015-06-30 | GSE53940 | GEO

Gene Expression profiling of rice leaves undergoing an innate immune response induced by XOO secreted cell wall degrading enzyme LipA (Lipase/Esterase A)

Project description:The plant cell wall degrading enzyme LipA (Lipase/Esterase A) is a Type II secretion system secreted protein of Xanthomonas oryzae pv. oryzae (Xoo; the casual of bacterial leaf blight of rice). LipA is an Xoo virulence factor. However, LipA is a double edged sword for Xoo as it induces rice defense responses such as programmed cell death/hypersensitive response like reaction (HR) and callose deposition. Prior treatment with LipA enhances resistance against subseqent Xoo infection. In order to understand the molecular events associated with Esterase (LipA) induced innate immune responsein rice , whole genome transcriptional profiling was performed using Affymetrix Rice GeneChips

2014-12-31 | GSE49242 | GEO

Targeting LIPA independent of its lipase activity is a therapeutic strategy in solid tumors via induction of endoplasmic reticulum stress.

| S-EPMC9325671 | biostudies-literature

TARGETING LIPA INDEPENDENT OF ITS LIPASE ACTIVITY IS A THERAPEUTIC STRATEGY IN SOLID TUMORS VIA INDUCTION OF ENDOPLASMIC RETICULUM STRESS

Project description:pCW57-LIPA-TurboID transduced cells were treated with or without 1mg/mL doxycycline for 48h, then were treated with 50mM biotin for 15min and then harvested and lysed in RIPA buffer (Thermo Scientific) supplemented with Halt protease inhibitor cocktail (Thermo Scientific) and Phosphatase Inhibitor Cocktail set I and set II (MilliporeSigma) on ice for 15min, followed by 20min of 20,000g centrifuge at 4 degrees C. Cleared cell lysates were incubated with M-270 streptavidin Dynabeads overnight. Then the beads were washed twice with RIPA buffer (2min), once with 1M KCl (2min), once with 0.1M Na2CO3 (10s), once with 2M urea in 10mM Tris-HCl (pH 8.0) (10s), and twice with RIPA buffer (2min). Enriched material was eluted from beads by boiling samples in 4x Laemmli buffer supplemented with 2mM biotin and 20mM DTT at 95 degrees C for 10min. Eluted samples were resolved in SDS-PAGE and followed by mass spectrometry by Lumos. biological replicate 1, 929193 (clone 1, no Dox.), 929194 (clone 1, with Dox.), 929196 (clone 2, no Dox.) and 929197 (clone 2, with Dox.). biological replicate 2, 932804 (clone 1, no Dox.), 932805 (clone 1, with Dox.), 932807 (clone 2, no Dox.) and 932808 (clone 2, with Dox.).

2022-03-23 | MSV000089108 | MassIVE

Ribosome footprinting in the cytosol and endoplasmic reticulum

Project description:In eukaryotic cells, the spatial regulation of protein expression is frequently conferred through the coupling of mRNA localization and the local control of translation. mRNA localization to the endoplasmic reticulum (ER) is a prominent example of such regulation and serves a ubiquitous role in segregating the synthesis of secretory and integral membrane proteins to the ER. Recent genomic and biochemical studies have now expanded this view to suggest a role for the ER in global protein synthesis. We have utilized cell fractionation and ribosome profiling to obtain a genomic survey of the subcellular organization of mRNA translation and report that ribosomal loading of mRNAs, a proxy for mRNA translation, is biased to the ER. Notably, ER-associated mRNAs encoding both cytosolic and topogenic signal-encoding proteins display similar ribosome loading densities, suggesting that ER-associated ribosomes serve a global role in mRNA translation. We propose that the partitioning of mRNAs and their translation between the cytosol and ER compartments may represent a novel mechanism for the post-transcriptional regulation of gene expression. HEK293 cells were fractionated between the cytosol and endoplasmic reticulum. Within each fraction, ribosome footprints were generated and sequenced. In parallel, total mRNA was sequenced.

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Tunicamycin-induced Endoplasmic Reticulum-Quality Control Pathway and Endoplasmic Reticulum-Associated Degradation Mechanism in the diatom Phaeodactylum tricornutum

Project description:Tunicamycin-induced Endoplasmic Reticulum-Quality Control Pathway and Endoplasmic Reticulum-Associated Degradation Mechanism in the diatom Phaeodactylum tricornutum

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EMD37 triggers endoplasmic reticulum stress in cancer cells

Project description:EMD37 triggers endoplasmic reticulum stress in cancer cells

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