Targeting Sphingolipid Metabolism in Head and Neck Cancer: Rational Therapeutic Potentials

Overview

Journal Expert Opin Ther Targets

Publisher Informa Healthcare

Specialty Pharmacology

Date 2010 Mar 26

PMID 20334489

Citations 15

Authors

Thomas H Beckham

Saeed Elojeimy

Joseph C Cheng

Lorianne S Turner

Stanley R Hoffman

James S Norris

Xiang Liu

Affiliations

Soon will be listed here.

Abstract

Importance Of The Field: Ceramide accumulation has been shown to be a conserved mechanism of apoptosis initiation in normal physiological processes as well as in response to cancer treatments. Therefore, it is unsurprising that many cancers develop aberrations of sphingolipid metabolism that prevent the accumulation of ceramide, whether by reduction of ceramide generation or by enhanced ceramide catabolism, particularly dangerous when catabolism leads to generation of pro-tumor sphingosine-1-phosphate and ceramide-1-phosphate. Numerous studies have now implicated dysregulation of sphingolipid metabolism in head and neck cancers.

Areas Covered In This Review: This review highlights the importance of sphingolipid metabolism and brings sphingolipid metabolism to the forefront in the investigation of novel therapies for head and neck cancer. It reviews sphingolipid-centric therapies under investigation in preclinical and clinical trials of cancers of the head and neck.

What The Reader Will Gain: The roles of sphingolipids and sphingolipid metabolism in cancer are reviewed and the reader will be brought up to date with discoveries in the field of sphingolipid metabolism in head and neck cancer.

Take Home Message: As treatments for head and neck cancers are currently limited, the potential of targeting sphingolipid metabolism should be taken into consideration as we seek novel ways to combat this group of tumors.

Citing Articles

Deciphering the role of sphingolipid metabolism in the immune microenvironment and prognosis of esophageal cancer via single-cell sequencing and bulk data analysis.

He R, Tang J, Lai H, Zhang T, Du L, Wei S Discov Oncol. 2024; 15(1):505.

PMID: 39333432 PMC: 11436545. DOI: 10.1007/s12672-024-01379-1.

Lipid metabolism reprogramming in head and neck cancer.

Liang J, Li L, Li L, Zhou X, Zhang Z, Huang Y Front Oncol. 2023; 13:1271505.

PMID: 37927468 PMC: 10622980. DOI: 10.3389/fonc.2023.1271505.

Natural Products and Small Molecules Targeting Cellular Ceramide Metabolism to Enhance Apoptosis in Cancer Cells.

Afrin F, Mateen S, Oman J, Lai J, Barrott J, Pashikanti S Cancers (Basel). 2023; 15(18).

PMID: 37760612 PMC: 10527029. DOI: 10.3390/cancers15184645.

The potential role of acid ceramidase in oral squamous cell carcinoma chemo-resistance by inducing autophagy.

Norouzi A, Davodabadi F, Noorbakhsh Varnosfaderani S, Zalpoor H Hum Cell. 2023; 36(6):2273-2275.

PMID: 37515715 DOI: 10.1007/s13577-023-00960-0.

Plasma metabolomics of oral squamous cell carcinomas based on NMR and MS approaches provides biomarker identification and survival prediction.

Polachini G, de Castro T, Smarra L, Henrique T, de Paula C, Severino P Sci Rep. 2023; 13(1):8588.

PMID: 37237049 PMC: 10220089. DOI: 10.1038/s41598-023-34808-2.

References

Kolesnick R . The therapeutic potential of modulating the ceramide/sphingomyelin pathway. J Clin Invest. 2002; 110(1):3-8. PMC: 151041. DOI: 10.1172/JCI16127. View

Shabbits J, Mayer L . Intracellular delivery of ceramide lipids via liposomes enhances apoptosis in vitro. Biochim Biophys Acta. 2003; 1612(1):98-106. DOI: 10.1016/s0005-2736(03)00108-1. View

Rath G, Schneider C, Langlois B, Sartelet H, Morjani H, Btaouri H . De novo ceramide synthesis is responsible for the anti-tumor properties of camptothecin and doxorubicin in follicular thyroid carcinoma. Int J Biochem Cell Biol. 2008; 41(5):1165-72. DOI: 10.1016/j.biocel.2008.10.021. View

Kawamori T, Osta W, Johnson K, Pettus B, Bielawski J, Tanaka T . Sphingosine kinase 1 is up-regulated in colon carcinogenesis. FASEB J. 2005; 20(2):386-8. DOI: 10.1096/fj.05-4331fje. View

Ruckhaberle E, Rody A, Engels K, Gaetje R, von Minckwitz G, Schiffmann S . Microarray analysis of altered sphingolipid metabolism reveals prognostic significance of sphingosine kinase 1 in breast cancer. Breast Cancer Res Treat. 2007; 112(1):41-52. DOI: 10.1007/s10549-007-9836-9. View

Hanada K, Kumagai K, Tomishige N, Yamaji T . CERT-mediated trafficking of ceramide. Biochim Biophys Acta. 2009; 1791(7):684-91. DOI: 10.1016/j.bbalip.2009.01.006. View

Lin S, Bassik M, Suh H, Nishino M, Arroyo J, Hahn W . PP2A regulates BCL-2 phosphorylation and proteasome-mediated degradation at the endoplasmic reticulum. J Biol Chem. 2006; 281(32):23003-12. DOI: 10.1074/jbc.M602648200. View

Xin M, Deng X . Protein phosphatase 2A enhances the proapoptotic function of Bax through dephosphorylation. J Biol Chem. 2006; 281(27):18859-67. DOI: 10.1074/jbc.M512543200. View

Liu X, Elojeimy S, El-Zawahry A, Holman D, Bielawska A, Bielawski J . Modulation of ceramide metabolism enhances viral protein apoptin's cytotoxicity in prostate cancer. Mol Ther. 2006; 14(5):637-46. DOI: 10.1016/j.ymthe.2006.06.005. View

10.

Chalfant C, Spiegel S . Sphingosine 1-phosphate and ceramide 1-phosphate: expanding roles in cell signaling. J Cell Sci. 2005; 118(Pt 20):4605-12. DOI: 10.1242/jcs.02637. View

11.

Gouaze V, Yu J, Bleicher R, Han T, Liu Y, Wang H . Overexpression of glucosylceramide synthase and P-glycoprotein in cancer cells selected for resistance to natural product chemotherapy. Mol Cancer Ther. 2004; 3(5):633-9. View

12.

Shen Y, Wang X, Xia W, Wang C, Cai M, Xie H . Antiproliferative and overadditive effects of rapamycin and FTY720 in pancreatic cancer cells in vitro. Transplant Proc. 2008; 40(5):1727-33. DOI: 10.1016/j.transproceed.2008.03.150. View

13.

Koybasi S, Senkal C, Sundararaj K, Spassieva S, Bielawski J, Osta W . Defects in cell growth regulation by C18:0-ceramide and longevity assurance gene 1 in human head and neck squamous cell carcinomas. J Biol Chem. 2004; 279(43):44311-9. DOI: 10.1074/jbc.M406920200. View

14.

Senkal C, Ponnusamy S, Rossi M, Sundararaj K, Szulc Z, Bielawski J . Potent antitumor activity of a novel cationic pyridinium-ceramide alone or in combination with gemcitabine against human head and neck squamous cell carcinomas in vitro and in vivo. J Pharmacol Exp Ther. 2006; 317(3):1188-99. DOI: 10.1124/jpet.106.101949. View

15.

Elojeimy S, Liu X, McKillop J, El-Zawahry A, Holman D, Cheng J . Role of acid ceramidase in resistance to FasL: therapeutic approaches based on acid ceramidase inhibitors and FasL gene therapy. Mol Ther. 2007; 15(7):1259-63. DOI: 10.1038/sj.mt.6300167. View

16.

Chmura S, Nodzenski E, Kharbanda S, Pandey P, Quintans J, Kufe D . Down-regulation of ceramide production abrogates ionizing radiation-induced cytochrome c release and apoptosis. Mol Pharmacol. 2000; 57(4):792-6. DOI: 10.1124/mol.57.4.792. View

17.

Azuma H, Takahara S, Ichimaru N, Wang J, Itoh Y, Otsuki Y . Marked prevention of tumor growth and metastasis by a novel immunosuppressive agent, FTY720, in mouse breast cancer models. Cancer Res. 2002; 62(5):1410-9. View

18.

Visentin B, Vekich J, Sibbald B, Cavalli A, Moreno K, Matteo R . Validation of an anti-sphingosine-1-phosphate antibody as a potential therapeutic in reducing growth, invasion, and angiogenesis in multiple tumor lineages. Cancer Cell. 2006; 9(3):225-38. DOI: 10.1016/j.ccr.2006.02.023. View

19.

Hannun Y, Obeid L . Ceramide: an intracellular signal for apoptosis. Trends Biochem Sci. 1995; 20(2):73-7. DOI: 10.1016/s0968-0004(00)88961-6. View

20.

Ishikawa A, Motohashi S, Ishikawa E, Fuchida H, Higashino K, Otsuji M . A phase I study of alpha-galactosylceramide (KRN7000)-pulsed dendritic cells in patients with advanced and recurrent non-small cell lung cancer. Clin Cancer Res. 2005; 11(5):1910-7. DOI: 10.1158/1078-0432.CCR-04-1453. View