Several in vitro studies have correlated dysfunction of the sphingolipid-signaling pathway with promotion of tumor cell growth as well as progression and resistance of tumors to chemotherapeutic agents. As ceramides (Cer) constitute the structural backbones of all sphingolipids, we investigated the endogenous ceramide levels in 43 malignant breast tumors and 21 benign breast biopsies and compared them with those of normal tissues using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). The total ceramide levels in malignant tumor tissue samples were statistically significantly elevated when compared with normal tissue samples. Upregulation of the total ceramide level averaged 12-fold and 4-fold higher than normal tissue samples, for malignant tumors and benign tissues, respectively. Specifically, the levels of C(16:0)-Cer, C(24:1)-Cer and C(24:0)-Cer were significantly raised in malignant tumors as compared with benign and normal tissue. The augmentation of the various ceramides could be assigned to an increase of the messenger RNA levels of ceramide synthases (CerS) LASS2 (longevity assurance), LASS4 and LASS6. Notably, elevated levels of C(16:0)-Cer were associated with a positive lymph node status, indicating a metastatic potential for this ceramide. Moreover, the levels of C(18:0)-Cer and C(20:0)-Cer were significantly higher in estrogen receptor (ER) positive tumor tissues as compared with ER negative tumor tissues. In conclusion, progression in breast cancer is associated with increased ceramide levels due to an upregulation of specific LASS genes.
Sphingolipids such as ceramides (Cers) play important roles in cell proliferation, apoptosis, and cell cycle regulation. An increased Cer level is linked to the cytotoxic effects of several chemotherapeutics. Various selective cyclooxygenase-2 (COX-2) inhibitors induce anti-proliferative effects in tumor cells. We addressed the possible interaction of the selective COX-2 inhibitors, coxibs, with the sphingolipid pathway as an explanation of their anti-proliferative effects. Sphingolipids were measured using liquid chromatography tandem mass spectrometry. Treatment of various cancer cell lines with celecoxib significantly increased sphinganine, C 16:0 -, C 24:0 -, C 24:1 -dihydroceramide (dhCer) and led to a depletion of C 24:0 -, C 24:1 -Cer in a time-and concentrationdependent manner, whereas other coxibs had no effect. Using 13 C, 15 N-labeled L-serine, we demonstrated that the augmented dhCers after celecoxib treatment originate from de novo synthesis. Celecoxib inhibited the dihydroceramide desaturase (DEGS) in vivo with an IC 50 of 78.9 6 1.5 mM and increased total Cer level about 2-fold, indicating an activation of sphingolipid biosynthesis. Interestingly, inhibition of the sphingolipid biosynthesis by specific inhibitors of L-serine palmitoyltransferase diminished the anti-proliferative potency of celecoxib. In conclusion, induction of de novo synthesis of sphingolipids and inhibition of DEGS contribute to the anti-proliferative effects of celecoxib.-Schiffmann, S., J. Sandner, R. Schmidt, K. Birod, I. Wobst, H. Schmidt, C. Angioni, G. Geisslinger, and S. Grösch. The selective COX-2 inhibitor celecoxib modulates sphingolipid synthesis. J. Lipid Res. 2009. 50: 32-40. Supplementary key words cancerSphingolipids constitute an essential component of the eucaryotic plasma membrane and are also utilized as an important second messenger in a variety of cellular events, including cell senescence, cellular differentiation, apoptosis, and proliferation (1-3). Endogenous sphingolipid levels can be controlled by activation of sphingomyelinases (SMases) and de novo synthesis as well as by specific degradation mechanisms (e.g., ceramidases, lyases). The sphingolipid biosynthesis commences in the endoplasmic reticulum with the condensation of palmitoyl-CoA and L-serine by L-serine palmitoyltransferase (L-SPT). The intermediate 3-ketosphinganine is rapidly converted into sphinganine (dhSph) by 3-ketosphinganine reductase. Acyl-CoA thioesters of variable chain lengths are then attached to dhSph by chain-length-specific (dihydro)ceramide synthases (CerSs) (4). Dihydroceramide desaturase (DEGS) introduces a 4, 5-trans double bond in dihydroceramides (dhCers), resulting in formation of the final product, Cer. Via sphingosine (Sph), Cer is metabolized by the enzymes ceramidase and sphingosine kinase to sphingosine-1-phosphate (Sph1P
Microsomal prostaglandin E(2)-synthase (mPGES-1) is a target for future anti-inflammatory drugs. Inhibitors of mPGES-1 mimicking prostaglandin E(2) often interact with cyclooxygenases (COXs) 1 and 2, leading to unwanted side effects. Selective inhibitors of mPGES-1 can be obtained by deliberate abdication of the acidic groups, which are an important feature of COX inhibition. Here, we present a successful virtual screening study that results in a potent nonacidic mPGES-1 inhibitor lacking COX inhibition.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.