The Expression Profile of Phosphatidylinositol in High Spatial Resolution Imaging Mass Spectrometry as a Potential Biomarker for Prostate Cancer

Goto, Takayuki; Terada, Naoki; Inoue, Takahiro; Nakayama, Kenji; Okada, Yoshiyuki; Yoshikawa, Takeshi; Miyazaki, Yu; Uegaki, Masayuki; Saito, Shinji; Kobayashi, Takashi; Kamba, Tomomi; Yoshimura, Koji; Ogawa, Osamu

doi:10.1371/journal.pone.0090242

Cited by 66 publications

(71 citation statements)

References 46 publications

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“…PIs are not considered to be rate-limiting for the formation of PIP n , and their roles in many cancers are yet to be defined. However, specific PIs have been proposed as biomarkers for prostate cancer (46), and have been shown to be elevated in human lung tumors (47). One possibility here is that PI may provide an alternative source of arachidonic acid, because the most abundant PI identified was arachidonatecontaining PI (38:4).…”

Section: Discussionmentioning

confidence: 99%

Myc Expression Drives Aberrant Lipid Metabolism in Lung Cancer

et al. 2016

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MYC-mediated pathogenesis in lung cancer continues to attract interest for new therapeutic strategies. In this study, we describe a transgenic mouse model of KRAS-driven lung adenocarcinoma that affords reversible activation of MYC, used here as a tool for lipidomic profiling of MYC-dependent lung tumors formed in this model. Advanced mass spectrometric imaging and surface analysis techniques were used to characterize the spatial and temporal changes in lipid composition in lung tissue. We found that normal lung tissue was characterized predominantly by saturated phosphatidylcholines and phosphatidylglycerols, which are major lipid components of pulmonary surfactant. In contrast, tumor tissues displayed an increase in phosphatidylinositols and arachidonate-containing phospholipids that can serve as signaling precursors. Deactivating MYC resulted in a rapid and dramatic decrease in arachidonic acid and its eicosanoid metabolites. In tumors with high levels of MYC, we found an increase in cytosolic phospholipase A2 (cPLA2) activity with a preferential release of membrane-bound arachidonic acid, stimulating the lipoxygenase (LOX) and COX pathways also amplified by MYC at the level of gene expression. Deactivating MYC lowered cPLA2 activity along with COX2 and 5-LOX mRNA levels. Notably, inhibiting the COX/5-LOX pathways in vivo reduced tumor burden in a manner associated with reduced cell proliferation. Taken together, our results show how MYC drives the production of specific eicosanoids critical for lung cancer cell survival and proliferation, with possible implications for the use of COX and LOX pathway inhibitors for lung cancer therapy.

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Section: Discussionmentioning

confidence: 99%

Myc Expression Drives Aberrant Lipid Metabolism in Lung Cancer

et al. 2016

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“…IMS was previously used to analyze intracellular phospholipids (Shimma et al, 2007;Snel and Fuller, 2010;Miyamura et al, 2011;Kawashima et al, 2013;Goto et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

“…Buck et al (2015) and Groseclose et al (2015) reported localization of SN-38, which is an active metabolite of a colon cancer drug, and deposition of dabrafenib in renal tubules from a toxicological study, respectively. Furthermore, a comparison of endogenous substrates between normal and tumorous tissues (Shimma et al, 2007;Kawashima et al, 2013;Goto et al, 2014), and changes in the endogenous substrates in response to drugs were also examined by IMS (Sun et al, 2016). Therefore, it is possible to evaluate susceptibility to DIPL by distinguishing mouse and human hepatocyte regions on the liver slices prepared from chimeric mice after the administration of amiodarone and analyzing hepatic localization of amiodarone, desethylamiodarone, and PhCs by IMS.…”

Section: Introductionmentioning

confidence: 99%

Assessment of amiodarone-induced phospholipidosis in chimeric mice with a humanized liver

et al. 2017

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-It is important to consider susceptibility to drug-induced toxicity between animals and humans. Chimeric mice with a humanized liver are expected to predict hepatotoxicity in humans. Druginduced phospholipidosis (DIPL), in which phospholipids accumulate, is a known entity. In this study, we examined whether chimeric mice can reveal species differences in DIPL. Changes in various phosphatidylcholine (PhC) molecules were investigated in the liver of chimeric mice after administering amiodarone, which induces phospholipidosis. Liquid chromatography-tandem mass spectrometry revealed that levels of PhCs tended to increase in the liver after administration of amiodarone. The liver of chimeric mice consists of human hepatocytes and residual mouse hepatocytes. We used imaging mass spectrometry (IMS) to evaluate the increase of PhCs in human and mouse hepatocytes after administration of amiodarone. IMS visualizes localization of endogenous and exogenous molecules in tissues. The IMS analysis suggested that the localized levels of several PhCs tended to be higher in the human hepatocytes than those in mouse hepatocytes, and PhC levels changed in response to amiodarone. Chimeric mice with a humanized liver will be useful to evaluate species differences in DIPL between mice and humans.

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“…Recently, high resolution MSI provided a significant advantage of autoradiography from the aspect of the drug metabolites (Fehniger et al 2011;Jirasko et al 2014;Liu et al 2013;Buck et al 2015) and demonstrated the distribution of a confirmed drug metabolite that possibly lead to the drug toxicity (Török et al 2015). The technology is today making important contributions in fields such as PK screening (Castellino et al 2013), novel pro-drug concepts (Nilsson et al 2010;Fehniger et al 2011), drug delivery systems (DDS) by micellar nanoparticle formulation (Swales et al 2014), biomarkers for PD (Yasunaga et al 2013;Shariatgorji et al 2014;Cobice et al 2013) as well as proteomics (Goto et al 2014;Ye et al 2014). MSI ultimately leads to a better understanding of ADME, PK/PD and TK/TD.…”

Section: Drug Metabolism and Pharmacokinetics (Dmpk)mentioning

confidence: 99%

Drug compound characterization by mass spectrometry imaging in cancer tissue

et al. 2015

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MALDI mass spectrometry imaging (MSI) provides a technology platform that allows the accurate visualization of unlabeled small molecules within the two-dimensional spaces of tissue samples. MSI has proven to be a powerful tool-box concept in the development of new drugs. MSI allows unlabeled drug compounds and drug metabolites to be detected and identified and quantified according to their mass-to-charge ratios (m/z) at high resolution in complex tissue environments. Such drug characterization in situ, by both spatial and temporal behaviors within tissue compartments, provide new understandings of the dynamic processes impacting drug uptake and metabolism at the local sites targeted by therapy. Further, MSI in combination with histology and immunohistochemistry, provides the added value of defining the context of cell biology present at the sites of drug localization thus providing invaluable information relating to treatment efficacy. In this report we provide mass spectrometry imaging data within various cancers such as malignant melanoma in patients administered with vemurafenib, a protein kinase inhibitor that is targeting BRAF mutated proteins and that has shown significant efficacy in restraining disease progression. We also provide an overview of other examples of the new generation of targeted drugs, and demonstrate the data on personalized medicine drugs localization within tumor compartments within in vivo models. In these cancer models we provide detailed data on drug and target protein co-localization of YCG185 and sunitinib. These drugs are targeting VEGFR2 within the angiogenesis mechanism. Our ability to resolve drug uptake at targeted sites of directed therapy provides important opportunities for increasing our understanding about the mode of action of drug activity within the environment of disease.

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The Expression Profile of Phosphatidylinositol in High Spatial Resolution Imaging Mass Spectrometry as a Potential Biomarker for Prostate Cancer

Cited by 66 publications

References 46 publications

Myc Expression Drives Aberrant Lipid Metabolism in Lung Cancer

Myc Expression Drives Aberrant Lipid Metabolism in Lung Cancer

Assessment of amiodarone-induced phospholipidosis in chimeric mice with a humanized liver

Drug compound characterization by mass spectrometry imaging in cancer tissue

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