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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: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE168800 | GEO | 2022/03/18

REPOSITORIES: GEO

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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 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

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

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

Rescue of lysosomal acid lipase deficiency in mice by AAV liver gene transfer

Project description:Lysosomal acid lipase deficiency (LAL-D) is an autosomal recessive disorder caused by mutation in LIPA gene, which results in fat accumulation in liver and spleen leading to multi-organ failure. The severe form of LAL-D (infantile-onset; ≤5% residual LAL activity), if left untreated, results in premature death within the first year of life due to failure to thrive and hepatic insufficiency. Enzyme replacement therapy is the only available supportive treatment consisting in weekly systemic injection of recombinant LAL. Here, we characterize a novel LAL-D mouse model and develop a curative gene therapy treatment based on the in vivo administration of recombinant AAV8 (rAAV8) vector encoding for human LIPA transgene under the control of hepatocyte-specific promoter. We define the minimal AAV dose required to rescue disease lethality and to produce and secrete sufficient LAL to correct cholesterol and triglycerides accumulation in liver, spleen, blood cells and plasma. Finally, using liver transcriptomic and biochemical analysis, we also show the impairment of mitochondria associated with LAL-D and its recovery by gene therapy. Overall, our in vivo gene therapy strategy achieves stable long-term LAL expression to correct disease phenotype in LAL-D mouse model and opens a new therapeutic option for LAL-D patients.

2024-06-01 | GSE252742 | GEO

CDK7-dependent Transcriptional Addiction in Triple-Negative Breast Cancer (Microarray)

Project description:Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer that exhibits extremely high levels of genetic complexity and yet a relatively uniform transcriptional program. We postulate that TNBC might be highly dependent on uninterrupted transcription of a key set of genes within this gene expression program and might therefore be exceptionally sensitive to inhibitors of transcription. Utilizing a novel kinase inhibitor and CRISPR/Cas9-mediated gene editing, we show here that triple-negative but not ER/PR+ breast cancer cells are exceptionally dependent on CDK7, a transcriptional cyclin-dependent kinase. TNBC cells are unique in their dependence on this transcriptional CDK and suffer apoptotic cell death upon CDK7 inhibition. An “Achilles cluster” of TNBC-specific genes are extremely sensitive to CDK7 inhibition and frequently associated with super-enhancers. We conclude that CDK7 mediates transcriptional addiction to a vital cluster of genes in TNBC and CDK7 inhibition may be useful therapy for this challenging cancer. Expression microarrays in H3K27ac in triple-negative breast cancer +/- treatment with covalent CDK7 inhibitor THZ1 treatment

2015-09-24 | E-GEOD-69106 | biostudies-arrayexpress

Hepatic Lysosomal Acid Lipase Overexpression Worsens Hepatic Inflammation in Mice Fed a Western Diet

Project description:Non-alcoholic fatty liver disease (NAFLD) is characterized by the accumulation of lipid droplets (LD) in hepatocytes. NAFLD development and progression is associated with an increase in hepatic cholesterol and decreased autophagy and lipophagy flux. Previous studies have shown that the expression of lysosomal acid lipase (gene=LIPA, protein=LAL), which can hydrolyze both triglyceride and cholesteryl esters, is inversely correlated with the severity of NAFLD. In addition, ablation of LAL activity results in profound NAFLD. Based on this, we predicted that overexpressing LIPA in the livers of mice fed a Western diet (FPC) would prevent the development of NAFLD. As expected, mice fed the FPC diet exhibited numerous markers of NAFLD including hepatomegaly, lipid accumulation, and inflammation. Unexpectedly, LAL overexpression did not attenuate steatosis and had only minor effects on neutral lipid composition. However, LAL overexpression exacerbated inflammatory gene expression and infiltration of immune cells in mice fed the FPC diet. LAL overexpression also resulted in abnormal phagosome accumulation and lysosomal lipid accumulation depending upon the dietary treatment. Hepatic overexpression of LAL drove immune cell infiltration and inflammation and did not attenuate the development of NAFLD suggesting that targeting LAL expression is not a viable route to treat NAFLD.

2021-11-03 | GSE180377 | GEO

Conserved Role of FOXC1 in TNBC is parallel to FOXA1 in ER+ Breast Cancer

Project description:Triple-negative breast cancer (TNBC) is characterized by lack of receptors, estrogen (ER), progesterone, and Her2, and standard receptor-targeted therapies are ineffective. FOXC1, a transcriptional factor aberrantly overexpressed in many cancers, drives growth, metastasis, and stem-cell-like properties in TNBC. However, the molecular function of FOXC1 is unknown, partly due to heterogeneity of TNBC. Here, we show that although FOXC1 regulates many cancer hallmarks in TNBC, its function is varied in different cell lines, highlighted by the differential response to CDK4/6 inhibitors upon FOXC1 loss. Despite this functional heterogeneity, we show that FOXC1 regulates key oncogenes and tumor suppressors and identify a set of core FOXC1 peaks conserved across TNBC cell lines. We identify the ER-associated and drug-targetable nuclear receptor NR2F2 as a cofactor of FOXC1. Finally, we show that core FOXC1 targets in TNBC are parallelly regulated by the pioneer factor FOXA1 and the nuclear receptor NR2F2 in ER+ breast cancer.

2024-07-03 | PXD053261 | Pride

Expression profiling of breast cancer samples from Institut Curie (Maire cohort) -- BrainArray CDF

Project description:Transcriptome analysis of 130 breast cancer samples (41 TNBC ; 30 Her2 ; 30 Luminal B and 29 Luminal A), 11 normal breast tissue samples and 14 TNBC cell lines.

2015-01-23 | GSE65212 | GEO

Expression profiling of breast cancer samples from Institut Curie (Maire cohort) --Affy CDF

Project description:Transcriptome analysis of 130 breast cancer samples (41 TNBC ; 30 Her2 ; 30 Luminal B and 29 Luminal A), 11 normal breast tissue samples and 14 TNBC cell lines.

2015-01-23 | GSE65194 | GEO

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