Dataset Information

Blockade of the Lysophosphatidylserine Lipase ABHD12 Potentiates Ferroptosis in Cancer Cells.

ABSTRACT: Ferroptosis is a type of cell death caused by the pathogenic accumulation of lipid hydroperoxides. Pharmacological mechanisms to induce ferroptosis may provide a way to kill cancer cells that are resistant to other forms of cell death like apoptosis. Nonetheless, the proteins that regulate ferroptotic sensitivity in cancer cells remain incompletely understood. Here, we screened a panel of inhibitors of serine hydrolases-an enzyme class important for regulating lipid metabolism-for potentiation of ferroptosis in HT1080 fibrosarcoma cells. We found that DO264, a selective inhibitor of the lyso- and ox-phosphatidylserine (PS) lipase ABHD12, enhances ferroptotic death caused by RSL3, an inhibitor of the lipid peroxidase GPX4. RSL3-induced ferroptosis was also potentiated by genetic disruption of ABHD12. Metabolomic experiments revealed that, in addition to elevated lyso-PS, ABHD12-inactivated cells show higher quantities of arachidonate (C20:4)-containing PS and 2-arachidonoyl glycerol, pointing to potential oxidation-sensitive lipid mediators of ferroptosis regulated by ABHD12.

SUBMITTER: Kathman SG

PROVIDER: S-EPMC7386317 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Blockade of the Lysophosphatidylserine Lipase ABHD12 Potentiates Ferroptosis in Cancer Cells.

Kathman Stefan G SG Boshart Julia J Jing Hui H Cravatt Benjamin F BF

ACS chemical biology 20200320 4

Ferroptosis is a type of cell death caused by the pathogenic accumulation of lipid hydroperoxides. Pharmacological mechanisms to induce ferroptosis may provide a way to kill cancer cells that are resistant to other forms of cell death like apoptosis. Nonetheless, the proteins that regulate ferroptotic sensitivity in cancer cells remain incompletely understood. Here, we screened a panel of inhibitors of serine hydrolases-an enzyme class important for regulating lipid metabolism-for potentiation o ...[more]

PMID: 32195565

Similar Datasets

Project description:BackgroundGlucose-6-phospate dehydrogenase (G6PD) is the limiting enzyme of the pentose phosphate pathway (PPP) correlated to cancer progression and drug resistance. We previously showed that G6PD inhibition leads to Endoplasmic Reticulum (ER) stress often associated to autophagy deregulation. The latter can be induced by target-based agents such as Lapatinib, an anti-HER2 tyrosine kinase inhibitor (TKI) largely used in breast cancer treatment.MethodsHere we investigate whether G6PD inhibition causes autophagy alteration, which can potentiate Lapatinib effect on cancer cells. Immunofluorescence and flow cytometry for LC3B and lysosomes tracker were used to study autophagy in cells treated with lapatinib and/or G6PD inhibitors (polydatin). Immunoblots for LC3B and p62 were performed to confirm autophagy flux analyses together with puncta and colocalization studies. We generated a cell line overexpressing G6PD and performed synergism studies on cell growth inhibition induced by Lapatinib and Polydatin using the median effect by Chou-Talay. Synergism studies were additionally validated with apoptosis analysis by annexin V/PI staining in the presence or absence of autophagy blockers.ResultsWe found that the inhibition of G6PD induced endoplasmic reticulum stress, which was responsible for the deregulation of autophagy flux. Indeed, G6PD blockade caused a consistent increase of autophagosomes formation independently from mTOR status. Cells engineered to overexpress G6PD became resilient to autophagy and resistant to lapatinib. On the other hand, G6PD inhibition synergistically increased lapatinib-induced cytotoxic effect on cancer cells, while autophagy blockade abolished this effect. Finally, in silico studies showed a significant correlation between G6PD expression and tumour relapse/resistance in patients.ConclusionsThese results point out that autophagy and PPP are crucial players in TKI resistance, and highlight a peculiar vulnerability of breast cancer cells, where impairment of metabolic pathways and autophagy could be used to reinforce TKI efficacy in cancer treatment.

Dataset Information

Blockade of the Lysophosphatidylserine Lipase ABHD12 Potentiates Ferroptosis in Cancer Cells.

Publications

Blockade of the Lysophosphatidylserine Lipase ABHD12 Potentiates Ferroptosis in Cancer Cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets