Sphingolipidomics of A2780 human ovarian carcinoma cells treated with synthetic retinoids

Abstract

This article is available online at http://www.jlr.org and ovarian cancers, neuroblastoma, lymphoma, and leukemia. Many pieces of evidence indicate a link between HPR's antitumor effect and the metabolism of sphingolipids in tumor cells. As for many other anticancer drugs, the studies in tumor cell lines indicated that apoptosis is the major cytotoxic mechanism for HPR [even if the toxic effect of HPR is likely very complex and at least in part due to nonapoptotic mechanisms ( 2, 3 )], and HPR-induced apoptosis in cancer cells has been ascribed to the increased cellular levels of ceramide, a sphingolipid mediator playing multiple roles in apoptotic signaling, elicited by HPR ( 4 ). The main metabolic mechanism responsible for HPR-induced production of ceramide is represented by de novo synthesis. Exposure to HPR of human neuroblastoma ( 5 ) and prostate cancer cells ( 6 ) resulted in a time-and dose-dependent increase in the activity of serine palmitoyltansferase and (dihydro)ceramide synthase, which catalyze early steps in the biosynthesis of ceramide and derived sphingolipids ( 7 ), and the treatment of cultured cells with pharmacological inhibitors of these enzymes was able to block HPR-induced ceramide increase ( 5,6,8 ). However, the effects of HPR on sphingolipid metabolism are probably much more complex and still poorly understood. For example, the possible role of sphingomyelin turnover due to the action of sphingomyelinases in the HPRelicited ceramide production is still controversial, and confl icting results have been reported ( 8, 9 ). In neuroblastoma Supplementary key words 4-HPR • fenretinide • 4-oxo-4-HPRThe synthetic retinoid N -(4-hydroxyphenyl)retinamide (fenretinide, HPR) is cytotoxic in vitro to a variety of cancer cell types, including neuroblastoma, breast, lung, prostate, and ovarian. Together with these in vitro studies, several animal experimentations and preclinical or clinical studies suggest that fenretinide might represent a promising antitumor agent. In particular, in a phase III breast cancer prevention trial, it has proven to be effective in reducing the incidence of second breast malignancies in premenopausal women, with a concomitant reduction of ovarian cancer incidence ( 1 ). Currently, HPR is under clinical trials for the cure of prostatic

Bioactive Sphingolipids in Response to Chemotherapy: A Scope on Leukemias

“…De novo pathway is suspected to be the important mechanism in this type of cytotoxicity as evidenced by the increased levels of dhCer which is the intermediate product of this pathway. A similar observation was done in ovarian cancer cells treated with synthetic retinoids [129]. In this study, mass spectrometry analysis identified more than 30 species of sphingolipids, dhCer species being in particular, increased upon drug treatment,.…”

Sphingosine Kinase Mediates Resistance to the Synthetic Retinoid N-(4-Hydroxyphenyl)retinamide in Human Ovarian Cancer Cells

“…Moreover, it has been demonstrated that dihydroceramide, rather than ceramide, accumulates in HPR-treated tumor cells, due to the inhibitory effect of this retinoid on dihydroceramide desaturase (22,24,37). Indeed we recently showed by electrospray ionization-MS analysis that dihydroceramide and not ceramide is increased upon treatment of A2780 cells with HPR (36). In addition, recent observations suggest that HPR cytotoxicity might at least in part due to the elevation of cellular sphinganine levels (24).…”

“…All together these data suggest that SK inhibition sensitized A2780/HPR cells to HPR-induced apoptosis. Because the antiproliferative and cytotoxic effect of HPR on A2780 cells is mediated by a HPR-induced elevation in cellular dihydroceramide levels (7,36), a higher SK activity in resistant cells might be responsible for a reduced capability to form dihydroceramide or ceramide (i.e. to a lower dihydroceramide/S1P ratio with respect to sensitive cells upon challenge with the drug).…”

“…Short-chain ceramide is cytotoxic for A2780 human ovarian carcinoma cells (7), and these cells respond to HPR treatment with a robust production of dihydroceramide (36), likely due to its increased biosynthesis, with a concomitant reduction of cell proliferation and induction of apoptosis. On the other hand, HPR induced a much lesser response in terms of dihydroceramide production in the derived HPR-resistant clonal cell line, A2780/HPR.…”

Inhibition of dihydroceramide desaturase activity by the sphingosine kinase inhibitor SKI II

“…Blockade of Des1 produces an increase in dihydroceramides (dhCers), which have emerged as bioactive lipids and the target of several drugs ( 34 ), including fenretinide. Several studies have shown that cells respond to fenretinide treatment with a robust production of dhCers (35)(36)(37)(38)(39)(40)(41)(42)(43)(44), and that this increase induces autophagy ( 45,46 ). Furthermore, experimental evidence exists on the connection between resistance to fenretinide and increased S1P production ( 38,44 ) due to an increased SK activity and SK1 mRNA and protein levels ( 38 ).…”