Autophagy paradox and ceramide

Levine, 2004, Development by self-digestion: molecular mechanisms and biological functions of autophagy, Dev. Cell, 6, 463, 10.1016/S1534-5807(04)00099-1 Yang, 2010, Eaten alive: a history of macroautophagy, Nat. Cell Biol., 12, 814, 10.1038/ncb0910-814 Klionsky, 2005, The molecular machinery of autophagy: unanswered questions, J. Cell Sci., 118, 7, 10.1242/jcs.01620 Kon, 2010, Chaperone-mediated autophagy in health and disease, FEBS Lett., 584, 1399, 10.1016/j.febslet.2009.12.025 Mizushima, 2011, Autophagy: renovation of cells and tissues, Cell, 147, 728, 10.1016/j.cell.2011.10.026 Yang, 2009, An overview of the molecular mechanism of autophagy, Curr. Top. Microbiol. Immunol., 335, 1 Yang, 2010, Mammalian autophagy: core molecular machinery and signaling regulation, Curr. Opin. Cell Biol., 22, 124, 10.1016/j.ceb.2009.11.014 Levine, 2008, Autophagy in the pathogenesis of disease, Cell, 132, 27, 10.1016/j.cell.2007.12.018 Tanida, 2011, Autophagy basics, Microbiol. Immunol., 55, 1, 10.1111/j.1348-0421.2010.00271.x Singh, 2011, Autophagy in the cellular energetic balance, Cell Metab., 13, 495, 10.1016/j.cmet.2011.04.004 Mizushima, 2008, Autophagy fights disease through cellular self-digestion, Nature, 451, 1069, 10.1038/nature06639 Choi, 2013, Autophagy in human health and disease, N. Engl. J. Med., 368, 651, 10.1056/NEJMra1205406 Pattingre, 2005, Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy, Cell, 122, 927, 10.1016/j.cell.2005.07.002 Gozuacik, 2004, Autophagy as a cell death and tumor suppressor mechanism, Oncogene, 23, 2891, 10.1038/sj.onc.1207521 Qu, 2007, Autophagy gene-dependent clearance of apoptotic cells during embryonic development, Cell, 128, 931, 10.1016/j.cell.2006.12.044 Wong, 2010, Autophagy gone awry in neurodegenerative diseases, Nat. Neurosci., 13, 805, 10.1038/nn.2575 Rubinsztein, 2011, Autophagy and aging, Cell, 146, 682, 10.1016/j.cell.2011.07.030 Levine, 2011, Autophagy in immunity and inflammation, Nature, 469, 323, 10.1038/nature09782 Mizumura, 2012, The emerging importance of autophagy in pulmonary diseases, Chest, 142, 1289, 10.1378/chest.12-0809 Kirshenbaum, 2012, Regulation of autophagy in the heart in health and disease, J. Cardiovasc. Pharmacol., 60, 109, 10.1097/FJC.0b013e31825f6faa Singh, 2009, Autophagy regulates lipid metabolism, Nature, 458, 1131, 10.1038/nature07976 Mah, 2012, Autophagy and cancer, Cold Spring Harb. Perspect. Biol., 4, a008821, 10.1101/cshperspect.a008821 Sridhar, 2012, Autophagy and disease: always two sides to a problem, J. Pathol., 226, 255, 10.1002/path.3025 Rubinsztein, 2012, Autophagy modulation as a potential therapeutic target for diverse diseases, Nat. Rev. Drug Discov., 11, 709, 10.1038/nrd3802 Hara, 2006, Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice, Nature, 441, 885, 10.1038/nature04724 Komatsu, 2006, Loss of autophagy in the central nervous system causes neurodegeneration in mice, Nature, 441, 880, 10.1038/nature04723 Kuma, 2004, The role of autophagy during the early neonatal starvation period, Nature, 432, 1032, 10.1038/nature03029 Maiuri, 2007, Self-eating and self-killing: crosstalk between autophagy and apoptosis, Nat. Rev. Mol. Cell Biol., 8, 741, 10.1038/nrm2239 Colell, 2007, GAPDH and autophagy preserve survival after apoptotic cytochrome c release in the absence of caspase activation, Cell, 129, 983, 10.1016/j.cell.2007.03.045 Liang, 2007, The energy sensing LKB1-AMPK pathway regulates p27 (kip1) phosphorylation mediating the decision to enter autophagy or apoptosis, Nat. Cell Biol., 9, 218, 10.1038/ncb1537 Gozuacik, 2007, Autophagy and cell death, Curr. Top. Dev. Biol., 78, 217, 10.1016/S0070-2153(06)78006-1 Galluzzi, 2012, Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012, Cell Death Differ., 19, 107, 10.1038/cdd.2011.96 Choi, 2012, Autophagy and cancer, Exp. Mol. Med., 44, 109, 10.3858/emm.2012.44.2.033 Lum, 2005, Growth factor regulation of autophagy and cell survival in the absence of apoptosis, Cell, 120, 237, 10.1016/j.cell.2004.11.046 Yu, 2006, Autophagic programmed cell death by selective catalase degradation, Proc. Natl. Acad. Sci. U. S. A., 103, 4952, 10.1073/pnas.0511288103 Levine, 2005, Autophagy in cell death: an innocent convict?, J. Clin. Invest., 115, 2679, 10.1172/JCI26390 Yousefi, 2006, Calpain-mediated cleavage of Atg5 switches autophagy to apoptosis, Nat. Cell Biol., 8, 1124, 10.1038/ncb1482 Berry, 2007, Growth arrest and autophagy are required for salivary gland cell degradation in Drosophila, Cell, 131, 1137, 10.1016/j.cell.2007.10.048 Sridhar, 2012, Autophagy and disease: always two sides to a problem, J. Pathol., 226, 255, 10.1002/path.3025 Saito, 1993, Detailed deletion mapping of chromosome 17q in ovarian and breast cancers: 2-cM region on 17q213 often and commonly deleted in tumors, Cancer Res., 53, 3382 Liang, 1999, Induction of autophagy and inhibition of tumorigenesis by beclin 1, Nature, 402, 672, 10.1038/45257 Gao, 1995, Loss of heterozygosity of the BRCA1 and other loci on chromosome 17q in human prostate cancer, Cancer Res., 55, 1002 Qu, 2003, Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene, J. Clin. Invest., 112, 1809, 10.1172/JCI20039 Yue, 2003, Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor, Proc. Natl. Acad. Sci. U. S. A., 100, 15077, 10.1073/pnas.2436255100 Janku, 2011, Autophagy as a target for anticancer therapy, Nat. Rev. Clin. Oncol., 8, 528, 10.1038/nrclinonc.2011.71 Martelli, 2007, Targeting the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin module for acute myelogenous leukemia therapy: from bench to bedside, Curr. Med. Chem., 14, 2009, 10.2174/092986707781368423 Karantza-Wadsworth, 2007, Autophagy mitigates metabolic stress and genome damage in mammary tumorigenesis, Genes Dev., 21, 1621, 10.1101/gad.1565707 Mathew, 2007, Autophagy suppresses tumor progression by limiting chromosomal instability, Genes Dev., 21, 1367, 10.1101/gad.1545107 Eskelinen, 2011, The dual role of autophagy in cancer, Curr. Opin. Pharmacol., 11, 294, 10.1016/j.coph.2011.03.009 Mathew, 2007, Role of autophagy in cancer, Nat. Rev. Cancer, 7, 961, 10.1038/nrc2254 White, 2012, Deconvoluting the context-dependent role for autophagy in cancer, Nat. Rev. Cancer, 12, 401, 10.1038/nrc3262 Komatsu, 2010, The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1, Nat. Cell Biol., 12, 213, 10.1038/ncb2021 Lau, 2010, A noncanonical mechanism of Nrf2 activation by autophagy deficiency: direct interaction between Keap1 and p62, Mol. Cell. Biol., 30, 3275, 10.1128/MCB.00248-10 Villeneuve, 2010, Regulation of the Nrf2-Keap1 antioxidant response by the ubiquitin proteasome system: an insight into cullin-ring ubiquitin ligases, Antioxid. Redox Signal., 13, 1699, 10.1089/ars.2010.3211 Moscat, 2009, p62 at the crossroads of autophagy, apoptosis, and cancer, Cell, 137, 1001, 10.1016/j.cell.2009.05.023 Mathew, 2009, Autophagy suppresses tumorigenesis through elimination of p62, Cell, 137, 1062, 10.1016/j.cell.2009.03.048 Young, 2009, Autophagy mediates the mitotic senescence transition, Genes Dev., 23, 798, 10.1101/gad.519709 Yang, 2011, Pancreatic cancers require autophagy for tumor growth, Genes Dev., 25, 717, 10.1101/gad.2016111 Guo, 2011, Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis, Genes Dev., 25, 460, 10.1101/gad.2016311 Chen, 2009, Role and regulation of autophagy in cancer, Biochim. Biophys. Acta, 1793, 1516, 10.1016/j.bbamcr.2008.12.013 Adiseshaiah, 2013, Synergistic combination therapy with nanoliposomal C6-ceramide and vinblastine is associated with autophagy dysfunction in hepatocarcinoma and colorectal cancer models, Cancer Lett., 337, 254, 10.1016/j.canlet.2013.04.034 Koppenol, 2011, Otto Warburg's contributions to current concepts of cancer metabolism, Nat. Rev. Cancer, 11, 325, 10.1038/nrc3038 Selak, 2005, Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase, Cancer Cell, 7, 77, 10.1016/j.ccr.2004.11.022 Thompson, 2009, Metabolic enzymes as oncogenes or tumor suppressors, N. Engl. J. Med., 360, 813, 10.1056/NEJMe0810213 Ogretmen, 2004, Biologically active sphingolipids in cancer pathogenesis and treatment, Nat. Rev. Cancer, 4, 604, 10.1038/nrc1411 Futerman, 2004, The complex life of simple sphingolipids, EMBO Rep., 5, 777, 10.1038/sj.embor.7400208 Ponnusamy, 2010, Sphingolipids and cancer: ceramide and sphingosine-1-phosphate in the regulation of cell death and drug resistance, Future Oncol., 6, 1603, 10.2217/fon.10.116 Merrill, 1988, Kinetics of long-chain (sphingoid) base biosynthesis in intact LM cells: effects of varying the extracellular concentrations of serine and fatty acid precursors of this pathway, Biochemistry, 27, 340, 10.1021/bi00401a051 Kang, 2010, Hypoxia-induced neuronal apoptosis is mediated by de novo synthesis of ceramide through activation of serine palmitoyltransferase, Cell. Signal., 22, 610, 10.1016/j.cellsig.2009.11.015 Hannun, 2002, The Ceramide-centric universe of lipid-mediated cell regulation: stress encounters of the lipid kind, J. Biol. Chem., 277, 25847, 10.1074/jbc.R200008200 Tafesse, 2006, The multigenic sphingomyelin synthase family, J. Biol. Chem., 281, 29421, 10.1074/jbc.R600021200 Stefanić, 2010, Glucosylceramide synthesis inhibition affects cell cycle progression, membrane trafficking, and stage differentiation in Giardia lamblia, J. Lipid Res., 51, 2527, 10.1194/jlr.M003392 Morales, 2007, Pharmacological inhibition or small interfering RNA targeting acid ceramidase sensitizes hepatoma cells to chemotherapy and reduces tumor growth in vivo, Oncogene, 26, 905, 10.1038/sj.onc.1209834 Park, 2006, Acid ceramidase and human disease, Biochim. Biophys. Acta, 1758, 2133, 10.1016/j.bbamem.2006.08.019 Selvam, 2013, Sphingosine kinase/sphingosine 1-phosphate signaling in cancer therapeutics and drug resistance, Handb. Exp. Pharmacol., 216, 3, 10.1007/978-3-7091-1511-4_1 Saddoughi, 2013, Diverse functions of ceramide in cancer cell death and proliferation, Adv. Cancer Res., 117, 37, 10.1016/B978-0-12-394274-6.00002-9 Saddoughi, 2008, Roles of bioactive sphingolipids in cancer biology and therapeutics, Subcell. Biochem., 49, 413, 10.1007/978-1-4020-8831-5_16 Nylund, 2006, Molecular features of phospholipids that affect glycolipid transfer protein-mediated galactosylceramide transfer between vesicles, Biochim. Biophys. Acta, 1758, 807, 10.1016/j.bbamem.2006.04.023 Hanada, 2009, CERT-mediated trafficking of ceramide, Biochim. Biophys. Acta, 1791, 684, 10.1016/j.bbalip.2009.01.006 Hanada, 2007, CERT and intracellular trafficking of ceramide, Biochim. Biophys. Acta, 1771, 644, 10.1016/j.bbalip.2007.01.009 Kumagai, 2005, CERT mediates intermembrane transfer of various molecular species of ceramides, J. Biol. Chem., 280, 6488, 10.1074/jbc.M409290200 Hanada, 2003, Molecular machinery for non-vesicular trafficking of ceramide, Nature, 426, 803, 10.1038/nature02188 D'Angelo, 2007, Glycosphingolipid synthesis requires FAPP2 transfer of glucosylceramide, Nature, 449, 62, 10.1038/nature06097 Bose, 1995, Ceramide synthase mediates daunorubicin-induced apoptosis: an alternative mechanism for generating death signals, Cell, 82, 405, 10.1016/0092-8674(95)90429-8 Jazwinski, 2002, LAG1 puts the focus on ceramide signaling, Int. J. Biochem. Cell Biol., 34, 1491, 10.1016/S1357-2725(02)00044-4 Pewzner-Jung, 2006, When do Lasses (longevity assurance genes) become CerS (ceramide synthases)?: insights into the regulation of ceramide synthesis, J. Biol. Chem., 281, 25001, 10.1074/jbc.R600010200 Venkataraman, 2002, Upstream of growth and differentiation factor 1 (uog1), a mammalian homolog of the yeast longevity assurance gene 1 (LAG1), regulates N-stearoyl-sphinganine (C18-(dihydro)ceramide) synthesis in a fumonisin B1-independent manner in mammalian cells, J. Biol. Chem., 277, 35642, 10.1074/jbc.M205211200 Lee, 1991, Expression of growth/differentiation factor 1 in the nervous system: conservation of a bicistronic structure, Proc. Natl. Acad. Sci. U. S. A., 88, 4250, 10.1073/pnas.88.10.4250 Mizutani, 2005, Mammalian Lass6 and its related family members regulate synthesis of specific ceramides, Biochem. J., 390, 263, 10.1042/BJ20050291 Kageyama-Yahara, 2006, Transmembrane topology of ceramide synthase in yeast, Biochem. J., 398, 585, 10.1042/BJ20060697 Spassieva, 2006, Necessary role for the Lag1p motif in (dihydro)ceramide synthase activity, J. Biol. Chem., 281, 33931, 10.1074/jbc.M608092200 Schulz, 2006, The CLN9 protein, a regulator of dihydroceramide synthase, J. Biol. Chem., 281, 2784, 10.1074/jbc.M509483200 Imgrund, 2009, Adult ceramide synthase 2 (CERS2)-deficient mice exhibit myelin sheath defects, cerebellar degeneration, and hepatocarcinomas, J. Biol. Chem., 284, 33549, 10.1074/jbc.M109.031971 Jennemann, 2012, Loss of ceramide synthase 3 causes lethal skin barrier disruption, Hum. Mol. Genet., 21, 586, 10.1093/hmg/ddr494 Russo, 2013, Myristate-derived d16:0 sphingolipids constitute a cardiac sphingolipid pool with distinct synthetic routes and functional properties, J. Biol. Chem., 288, 13397, 10.1074/jbc.M112.428185 Young, 2013, Sphingolipids: regulators of crosstalk between apoptosis and autophagy, J. Lipid Res., 54, 5, 10.1194/jlr.R031278 Schubert, 2000, Ceramide inhibits protein kinase B/Akt by promoting dephosphorylation of serine 473, J. Biol. Chem., 275, 13330, 10.1074/jbc.275.18.13330 Scarlatti, 2004, Ceramide-mediated macroautophagy involves inhibition of protein kinase B and up-regulation of beclin 1, J. Biol. Chem., 279, 18384, 10.1074/jbc.M313561200 Zhou, 1998, Inhibition of Akt kinase by cell-permeable ceramide and its implications for ceramide-induced apoptosis, J. Biol. Chem., 273, 16568, 10.1074/jbc.273.26.16568 Ogretmen, 2002, Biochemical mechanisms of the generation of endogenous long chain ceramide in response to exogenous short chain ceramide in the A549 human lung adenocarcinoma cell line. Role for endogenous ceramide in mediating the action of exogenous ceramide, J. Biol. Chem., 277, 12960, 10.1074/jbc.M110699200 Guenther, 2009, A new take on ceramide: starving cells by cutting off the nutrient supply, Cell Cycle, 8, 1122, 10.4161/cc.8.8.8161 Peralta, 2009, Ceramide-induced starvation triggers homeostatic autophagy, Autophagy, 5, 407, 10.4161/auto.5.3.7809 Edinger, 2009, Starvation in the midst of plenty: making sense of ceramide-induced autophagy by analysing nutrient transporter expression, Biochem. Soc. Trans., 37, 253, 10.1042/BST0370253 Guenther, 2008, Ceramide starves cells to death by downregulating nutrient transporter proteins, Proc. Natl. Acad. Sci. U. S. A., 105, 17402, 10.1073/pnas.0802781105 Kang, 2011, The Beclin 1 network regulates autophagy and apoptosis, Cell Death Differ., 18, 571, 10.1038/cdd.2010.191 Liang, 1999, Induction of autophagy and inhibition of tumorigenesis by beclin 1, Nature, 402, 672, 10.1038/45257 Li, 2009, The pivotal role of c-Jun NH2-terminal kinase-mediated Beclin 1 expression during anticancer agents-induced autophagy in cancer cells, Oncogene, 28, 886, 10.1038/onc.2008.441 Bedia, 2011, Regulation of autophagy by sphingolipids, Anticancer Agents Med. Chem., 11, 844, 10.2174/187152011797655131 Daido, 2004, Pivotal role of the cell death factor BNIP3 in ceramide-induced autophagic cell death in malignant glioma cells, Cancer Res., 64, 4286, 10.1158/0008-5472.CAN-03-3084 Mammucari, 2007, FoxO3 controls autophagy in skeletal muscle in vivo, Cell Metab., 6, 458, 10.1016/j.cmet.2007.11.001 Zhang, 2008, Mitochondrial autophagy Is an HIF-1-dependent adaptive metabolic response to hypoxia, J. Biol. Chem., 283, 10892, 10.1074/jbc.M800102200 Spassieva, 2009, Disruption of ceramide synthesis by CerS2 down-regulation leads to autophagy and the unfolded protein response, Biochem. J., 424, 273, 10.1042/BJ20090699 Russo, 2012, Ceramide synthase 5 mediates lipid-induced autophagy and hypertrophy in cardiomyocytes, J. Clin. Invest., 122, 3919, 10.1172/JCI63888 Sentelle, 2012, Ceramide targets autophagosomes to mitochondria and induces lethal mitophagy, Nat. Chem. Biol., 8, 831, 10.1038/nchembio1212-1008c Gagliostro, 2012, Dihydroceramide delays cell cycle G1/S transition via activation of ER stress and induction of autophagy, Int. J. Biochem. Cell Biol., 44, 2135, 10.1016/j.biocel.2012.08.025 Signorelli, 2009, Dihydroceramide intracellular increase in response to resveratrol treatment mediates autophagy in gastric cancer cells, Cancer Lett., 282, 238, 10.1016/j.canlet.2009.03.020 Devlin, 2011, Dihydroceramide-based response to hypoxia, J. Biol. Chem., 286, 38069, 10.1074/jbc.M111.297994 Jiang, 2012, Gamma-tocotrienol induces apoptosis and autophagy in prostate cancer cells by increasing intracellular dihydrosphingosine and dihydroceramide, Int. J. Cancer, 130, 685, 10.1002/ijc.26054 Zheng, 2006, Ceramides and other bioactive sphingolipid backbones in health and disease: lipidomic analysis, metabolism and roles in membrane structure, dynamics, signaling and autophagy, Biochim. Biophys. Acta, 1758, 1864, 10.1016/j.bbamem.2006.08.009 Signorelli, 2009, Dihydroceramide intracellular increase in response to resveratrol treatment mediates autophagy in gastric cancer cells, Cancer Lett., 282, 238, 10.1016/j.canlet.2009.03.020 Huang, 2010, Celecoxib-induced apoptosis is enhanced by ABT-737 and by inhibition of autophagy in human colorectal cancer cells, Autophagy, 6, 256, 10.4161/auto.6.2.11124 Schiffmann, 2009, The selective COX-2 inhibitor celecoxib modulates sphingolipid synthesis, J. Lipid Res., 50, 32, 10.1194/jlr.M800122-JLR200 Grösch, 2012, Chain length-specific properties of ceramides, Prog. Lipid Res., 51, 50, 10.1016/j.plipres.2011.11.001 Jana, 2009, Ceramide and neurodegeneration: susceptibility of neurons and oligodendrocytes to cell damage and death, J. Neurol. Sci., 278, 5, 10.1016/j.jns.2008.12.010 Park, 2008, Vorinostat and sorafenib increase ER stress, autophagy and apoptosis via ceramide-dependent CD95 and PERK activation, Cancer Biol. Ther., 7, 1648, 10.4161/cbt.7.10.6623 Zhang, 2008, Multiple cyclin kinase inhibitors promote bile acid-induced apoptosis and autophagy in primary hepatocytes via p53-CD95-dependent signaling, J. Biol. Chem., 283, 24343, 10.1074/jbc.M803444200 Bursch, 1996, Active cell death induced by the anti-estrogens tamoxifen and ICI 164 384 in human mammary carcinoma cells (MCF-7) in culture: the role of autophagy, Carcinogenesis, 17, 1595, 10.1093/carcin/17.8.1595 Pattingre, 2009, Ceramide-induced autophagy: to junk or to protect cells?, Autophagy, 5, 558, 10.4161/auto.5.4.8390 Samaddar, 2008, A role for macroautophagy in protection against 4-hydroxytamoxifen-induced cell death and the development of antiestrogen resistance, Mol. Cancer Ther., 7, 2977, 10.1158/1535-7163.MCT-08-0447 Lavieu, 2007, Is autophagy the key mechanism by which the sphingolipid rheostat controls the cell fate decision?, Autophagy, 3, 45, 10.4161/auto.3416 Dbaibo, 2007, Arsenic trioxide induces accumulation of cytotoxic levels of ceramide in acute promyelocytic leukemia and adult T-cell leukemia/lymphoma cells through de novo ceramide synthesis and inhibition of glucosylceramide synthase activity, Haematologica, 92, 753, 10.3324/haematol.10968 Qian, 2007, Arsenic trioxide induces not only apoptosis but also autophagic cell death in leukemia cell lines via up-regulation of Beclin-1, Leuk. Res., 31, 329, 10.1016/j.leukres.2006.06.021 Yacoub, 2010, PERK-dependent regulation of ceramide synthase 6 and thioredoxin play a key role in mda-7/IL-24-induced killing of primary human glioblastoma multiforme cells, Cancer Res., 70, 1120, 10.1158/0008-5472.CAN-09-4043 Patschan, 2008, Lipid mediators of autophagy in stress-induced premature senescence of endothelial cells, Am. J. Physiol. Heart Circ. Physiol., 294, H1119, 10.1152/ajpheart.00713.2007 Taniguchi, 2012, Regulation of autophagy and its associated cell death by “sphingolipid rheostat”: reciprocal role of ceramide and sphingosine 1-phosphate in the mammalian target of rapamycin pathway, J. Biol. Chem., 287, 39898, 10.1074/jbc.M112.416552 Hou, 2011, Mitochondrially targeted ceramides preferentially promote autophagy, retard cell growth, and induce apoptosis, J. Lipid Res., 52, 278, 10.1194/jlr.M012161 Salazar, 2009, Cannabinoid action induces autophagy-mediated cell death through stimulation of ER stress in human glioma cells, J. Clin. Invest., 119, 1359, 10.1172/JCI37948 Chang, 2009, S1P5 is required for sphingosine 1-phosphate-induced autophagy in human prostate cancer PC-3 cells, Am. J. Physiol. Cell Physiol., 297, C451, 10.1152/ajpcell.00586.2008 Lavieu, 2006, Regulation of autophagy by sphingosine kinase 1 and its role in cell survival during nutrient starvation, J. Biol. Chem., 281, 8518, 10.1074/jbc.M506182200 Lépine, 2010, Sphingosine-1-phosphate phosphohydrolase-1 regulates ER stress-induced autophagy, Cell Death Differ., 18, 350, 10.1038/cdd.2010.104 Yester, 2011, Extracellular and intracellular sphingosine-1-phosphate in cancer, Cancer Metastasis Rev., 30, 577, 10.1007/s10555-011-9305-0 Van Brocklyn, 2012, The control of the balance between ceramide and sphingosine-1-phosphate by sphingosine kinase: oxidative stress and the seesaw of cell survival and death, Comp. Biochem. Physiol. B Biochem. Mol. Biol., 163, 26, 10.1016/j.cbpb.2012.05.006 Senkal, 2010, Antiapoptotic roles of ceramide-synthase-6-generated C16-ceramide via selective regulation of the ATF6/CHOP arm of ER-stress–response pathways, FASEB J., 24, 296, 10.1096/fj.09-135087 Karahatay, 2007, Clinical relevance of ceramide metabolism in the pathogenesis of human head and neck squamous cell carcinoma (HNSCC): attenuation of C(18)-ceramide in HNSCC tumors correlates with lymphovascular invasion and nodal metastasis, Cancer Lett., 256, 101, 10.1016/j.canlet.2007.06.003 Ryland, 2011, Dysregulation of sphingolipid metabolism in cancer, Cancer Biol. Ther., 11, 138, 10.4161/cbt.11.2.14624 Senkal, 2007, Role of human longevity assurance gene 1 and C18-ceramide in chemotherapy-induced cell death in human head and neck squamous cell carcinomas, Mol. Cancer Ther., 6, 712, 10.1158/1535-7163.MCT-06-0558 Saddoughi, 2011, Results of a phase II trial of gemcitabine plus doxorubicin in patients with recurrent head and neck cancers: serum C₁₈-ceramide as a novel biomarker for monitoring response, Clin. Cancer Res., 17, 6097, 10.1158/1078-0432.CCR-11-0930 Kester, 2003, Sphingolipids as therapeutics, Pharmacol. Res., 47, 365, 10.1016/S1043-6618(03)00048-3 Barth, 2011, Ceramide-based therapeutics for the treatment of cancer, Anticancer Agents Med. Chem., 11, 911, 10.2174/187152011797655177