Phospholipids of tumor extracellular vesicles stratify gefitinib-resistant nonsmall cell lung cancer cells from gefitinib-sensitive cells

Jung, Jae Hun; Lee, Min Young; Choi, Dong‐Hee; Lee, Jae Won; You, Sungyong; Lee, Kye Young; Kim, Jayoung; Kim, Kwang Pyo

doi:10.1002/pmic.201400243

Cited by 43 publications

(31 citation statements)

References 62 publications

(72 reference statements)

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“…These data, as well as previous studies demonstrates that there are fundamental differences between the lipidome of non-cancer and cancer cells [44,[59][60][61]. Non-cancer cells typically exhibit neutral total membrane charge due to the presence of zwitterionic phospholipids (PC and SM) on the outer leaflet of the membrane and PS and PE located in the inner leaflet of the membrane [62][63][64].…”

Section: Discussionsupporting

confidence: 82%

Identification of Lipidomic Profiles Associated with Drug-Resistant Prostate Cancer Cells

Ingram

Mansoura

Chou³

et al. 2020

Preprint

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BackgroundThe association of circulating lipids with clinical outcomes of drug-resistant castration-resistant prostate cancer (CRPC) is not fully understood. While it is known that increases in select lipids correlates to decreased survival, neither the mechanisms mediating these alterations nor the correlation of resistance to drug treatments are well characterized.MethodsWe addressed this gap-in-knowledge using in vitro models of non-cancerous, hormone-sensitive, CRPC and drug-resistant cell lines combined with quantitative LC-ESI-Orbitrap-MS lipidomic analysis and subsequent analysis such as Metaboanalyst and Lipid Pathway Enrichment (LIPEA).ResultsThis approach identified several lipid regulatory pathways associated with Docetaxel resistance in PCa. These included those controlling glycerophospholipid metabolism, sphingolipid signaling pathways and ferroptosis. In total, 7,460 features were identified as being dysregulated between the cell lines studied, and 21 lipid species were significantly altered in drug-resistant cell lines as compared to nonresistant cell lines. Docetaxel resistance cells (PC3-Rx and DU145-DR) and had higher levels of phosphatidylcholine (PC), oxidized lipid species, phosphatidylethanolamine (PE), and sphingomyelin (SM) as compared to parent control cells (PC-3 and DU-145). These cells also had higher levels of ceramides release into the media.ConclusionThese data identify lipids whose levels may correlate to Docetaxel sensitivity and progression of prostate cancer.

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Section: Discussionsupporting

confidence: 82%

Identification of Lipidomic Profiles Associated with Drug-Resistant Prostate Cancer Cells

Ingram

Mansoura

Chou³

et al. 2020

Preprint

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“…x TRMOME-1059; No. of Pages 10 resistant NSCLC[85]. The authors suggest that the phospholipid metabolism in EVs may represent a tumor phenotype and could be relevant to gefitinib resistance.…”

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confidence: 96%

Extracellular vesicles in lung microenvironment and pathogenesis

Fujita¹,

Kosaka²,

Araya³

et al. 2015

Trends in Molecular Medicine

159

142

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“…From the MALDI-MS spectra of lipids, we could distinguish DLD-1 and DLD-1/5-FU cells with a 60.8% and 86.9% confidence interval in both positive and negative ion modes, respectively. Each lipid was identified based on the search results of the precursor ion through Lipidomics Gateway (http:// www.lipidmaps.org) and the MS/MS fragment ions 19,20 through LIFT mode. Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Comparative lipidomics of 5-Fluorouracil–sensitive and –resistant colorectal cancer cells reveals altered sphingomyelin and ceramide controlled by acid sphingomyelinase (SMPD1)

Jung

Taniguchi

Lee

et al. 2020

Sci Rep

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5-Fluorouracil (5-FU)is a chemotherapeutic drug widely used to treat colorectal cancer. 5-FU is known to gradually lose its efficacy in treating colorectal cancer following the acquisition of resistance. We investigated the mechanism of 5-FU resistance using comprehensive lipidomic approaches. We performed lipidomic analysis on 5-FU-resistant (DLD-1/5-FU) and -sensitive (DLD-1) colorectal cancer cells using MALDI-MS and LC-MRM-MS. In particular, sphingomyelin (SM) species were significantly up-regulated in 5-FU-resistant cells in MALDI-TOF analysis. Further, we quantified sphingolipids including SM and Ceramide (Cer) using Multiple Reaction Monitoring (MRM), as they play a vital role in drug resistance. We found that 5-FU resistance in DLD-1/5-FU colorectal cancer cells was mainly associated with SM increase and Cer decrease, which are controlled by acid sphingomyelinase (SMPD1). In addition, reduction of SMPD1 expression was confirmed by LC-MRM-MS analysis and the effect of SMPD1 in drug resistance was assessed by treating DLD-1 cells with siRNA-SMPD1. Furthermore, clinical colorectal cancer data set analysis showed that down-regulation of SMPD1 was associated with resistance to chemotherapy regimens that include 5-FU. Thus, from our study, we propose that SM/Cer and SMPD1 are new potential target molecules for therapeutic strategies to overcome 5-FU resistance.Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality in both men and women 1 . Although there are other drugs for treatment of CRC, 5-Fluorouracil (5-FU) is widely used and is positioned as a first-line chemotherapy. 5-FU was developed as an inhibitor of thymidylate synthase (TS), which results in suppression of thymine synthase, resulting in cell death 2 . The mechanism involves misincorporation of a pyrimidine analogue into RNA and DNA in place of uracil or thymine, respectively 3 . Despite the effectiveness of 5-FU, drug resistance remains a significant limitation. To overcome this drug resistance, many researchers have tried to identify potential genes and proteins involved in mediating 5-FU resistance, using emerging technologies such as microarray profiling 4 and whole genome sequencing 5 . For instance, the alteration of drug influx and efflux by the ABCC5 membrane protein and mutation of the drug target 6 may lead to 5-FU resistance. Furthermore, accumulation of TS protein and elevated activity of deoxyuridine triphosphatase are expected to cause 5-FU resistance www.nature.com/scientificreports www.nature.com/scientificreports/ in CRC. Although various target genes are involved, the detailed 5-FU-resistance mechanism has not been fully elucidated. Therefore, new strategies for therapy and resistance reversal are urgently needed.Various lipidomic approaches have revealed that lipids play key roles in various phenomena in living cells including oncogenesis 7,8 , apoptosis 9 , and drug resistance 10-12 . Alterations in levels of glycerophospholipids (GPs) such as phosphatidylcholine (PC) and phosphatidylethanolamine (PE) h...

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Phospholipids of tumor extracellular vesicles stratify gefitinib-resistant nonsmall cell lung cancer cells from gefitinib-sensitive cells

Cited by 43 publications

References 62 publications

Identification of Lipidomic Profiles Associated with Drug-Resistant Prostate Cancer Cells

Identification of Lipidomic Profiles Associated with Drug-Resistant Prostate Cancer Cells

Extracellular vesicles in lung microenvironment and pathogenesis

Comparative lipidomics of 5-Fluorouracil–sensitive and –resistant colorectal cancer cells reveals altered sphingomyelin and ceramide controlled by acid sphingomyelinase (SMPD1)

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