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Series GSE168800 Query DataSets for GSE168800
Status Public on Mar 18, 2022
Title Targeting LIPA independent of its lipase activity is a therapeutic strategy in solid tumors via induction of endoplasmic reticulum stress
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Summary 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.
Overall design MDA-MB-231 and BT-549 cells were cultured in RPMI1640 (Gibco) supplemented with 10% FBS, 0.2% Normocin and 1% penicillin-streptomycin. SUM-159 cells were cultured in F-12 (Gibco) supplemented with 10% FBS, 0.2% Normocin and 1% penicillin-streptomycin.
Cells were treated with DMSO or ERX-41. For mRNAseq samples, ERX-41 treated cells were treated with 1 uM of ERX-41 for 2 or 4 hours. For CRISPR screen samples, ERX-41 treated cells were treated with 0.25 uM (1st screen) or 0.5 uM (2nd screen) for 3 weeks.
Web link
Contributor(s) Liu X, Raj GV
Citation(s) 35654861
Submission date Mar 12, 2021
Last update date Jun 05, 2022
Contact name Ganesh V. Raj
Organization name UT Southwestern Medical Center
Department Urology
Street address 5323 Harry Hines Blvd., JA5.150
City Dallas
State/province TX
ZIP/Postal code 75390-9111
Country USA
Platforms (1)
GPL18573 Illumina NextSeq 500 (Homo sapiens)
Samples (30)
GSM5170181 mRNA_231_Veh_rep_1
GSM5170182 mRNA_231_Veh_rep_2
GSM5170183 mRNA_231_2h_rep_1
BioProject PRJNA714060
SRA SRP310406

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SOFT formatted family file(s) SOFTHelp
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Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE168800_159_countTable.fpkm.txt.gz 1.7 Mb (ftp)(http) TXT
GSE168800_231_countTable.fpkm.txt.gz 1.3 Mb (ftp)(http) TXT
GSE168800_549_countTable.fpkm.txt.gz 1.3 Mb (ftp)(http) TXT
GSE168800_Screen1.pdf 201.0 Kb (ftp)(http) PDF
GSE168800_Screen2.pdf 205.9 Kb (ftp)(http) PDF
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Raw data are available in SRA
Processed data are available on Series record

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