Targeting glucosylceramide synthase upregulation reverts sorafenib resistance in experimental hepatocellular carcinoma

Oncotarget

Volumn 7, Issue 7, 2016, Pages 8253-8267

  Stefanovic, Milica ^a   Tutusaus, Anna ^a   Martinez Nieto, Guillermo A ^a   Bárcena, Cristina ^a   De Gregorio, Estefania ^a   Moutinho, Catia ^b   Barbero Camps, Elisabet ^a   Villanueva, Alberto ^b   Colell, Anna ^a   Marí, Montserrat ^a   García Ruiz, Carmen ^a,c   Fernandez Checa, Jose C ^a,c,d   Morales, Albert ^a  

^a INSTITUT D INVESTIGACIONS BIOMÈDIQUES AUGUST PI I SUNYER IDIBAPS   (Spain)

^b BELLVITGE BIOMEDICAL RESEARCH INSTITUTE IDIBELL   (Spain)

^c HOSPITAL CLÍNIC   (Spain)

^d UNIVERSITY OF SOUTHERN CALIFORNIA   (United States)

Author keywords

Ceramide; Chemotherapy; Liver cancer; Mitochondria; Mouse model

Indexed keywords

2 DECANOYLAMINO 3 MORPHOLINO 1 PHENYL 1 PROPANOL; 3 METHYLADENINE; ADENOSINE TRIPHOSPHATE; BAFILOMYCIN A1; BENZYLOXYCARBONYLVALYLALANYLASPARTYL FLUOROMETHYL KETONE; CERAMIDE; CERAMIDE GLUCOSYLTRANSFERASE; CYTOCHROME C; IMIPRAMINE; SORAFENIB; THERMOZYMOCIDIN; CARBANILAMIDE DERIVATIVE; GLUCOSYLTRANSFERASE; IMMUNOSUPPRESSIVE AGENT; MESSENGER RNA; MONOUNSATURATED FATTY ACID; NICOTINAMIDE; PROTEIN KINASE INHIBITOR;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CELL DEATH; CELLULAR DISTRIBUTION; CONTROLLED STUDY; DRUG EFFICACY; DRUG TARGETING; ENZYME INDUCTION; ENZYME INHIBITION; EXPERIMENTAL NEOPLASM; GENE OVEREXPRESSION; GENE SILENCING; HEPATOMA CELL; HEPG2 CELL LINE; HUMAN; HUMAN CELL; LIVER CELL CARCINOMA; MALE; MITOCHONDRION; MOUSE; NONHUMAN; UPREGULATION; ANALOGS AND DERIVATIVES; ANIMAL; ANTAGONISTS AND INHIBITORS; APOPTOSIS; CARCINOMA, HEPATOCELLULAR; CELL PROLIFERATION; DRUG EFFECTS; DRUG RESISTANCE; DRUG SCREENING; ENZYME IMMUNOASSAY; ENZYMOLOGY; GENE EXPRESSION REGULATION; GENETICS; LIVER NEOPLASMS, EXPERIMENTAL; METABOLISM; NUDE MOUSE; PATHOLOGY; REAL TIME POLYMERASE CHAIN REACTION; REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION; SIGNAL TRANSDUCTION; TUMOR CELL CULTURE; WESTERN BLOTTING;

ANIMALS; APOPTOSIS; BLOTTING, WESTERN; CARCINOMA, HEPATOCELLULAR; CELL PROLIFERATION; CERAMIDES; DRUG RESISTANCE, NEOPLASM; FATTY ACIDS, MONOUNSATURATED; GENE EXPRESSION REGULATION, ENZYMOLOGIC; GENE EXPRESSION REGULATION, NEOPLASTIC; GLUCOSYLTRANSFERASES; HUMANS; IMMUNOENZYME TECHNIQUES; IMMUNOSUPPRESSIVE AGENTS; LIVER NEOPLASMS, EXPERIMENTAL; MALE; MICE; MICE, NUDE; NIACINAMIDE; PHENYLUREA COMPOUNDS; PROTEIN KINASE INHIBITORS; REAL-TIME POLYMERASE CHAIN REACTION; REVERSE TRANSCRIPTASE POLYMERASE CHAIN REACTION; RNA, MESSENGER; SIGNAL TRANSDUCTION; TUMOR CELLS, CULTURED; XENOGRAFT MODEL ANTITUMOR ASSAYS;

EID: 84958787106     PISSN: None     EISSN: 19492553     Source Type: Journal    
DOI: 10.18632/oncotarget.6982     Document Type: Article

References (48)

1. Villanueva A, Llovet JM. Liver cancer in 2013: Mutational landscape of HCC--the end of the beginning. Nat Rev Clin Oncol. 2014; 11:73-74.
2. Michelotti GA, Machado MV, Diehl AM. NAFLD, NASH and liver cancer. Nat Rev Gastroenterol Hepatol. 2013; 10:656-665.
3. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008; 359:378-390.
4. Wörns MA, Galle PR. HCC therapies--lessons learned. Nat Rev Gastroenterol Hepatol. 2014; 11:447-452.
5. Berasain C. Hepatocellular carcinoma and sorafenib: too many resistance mechanisms? Gut. 2013; 62:1674-1675.
6. Llovet JM, Hernandez-Gea V. Hepatocellular carcinoma: reasons for phase III failure and novel perspectives on trial design. Clin Cancer Res. 2014; 20:2072-2079.
7. Hannun YA, Obeid LM. Principles of bioactive lipid signalling: lessons from sphingolipids. Nat Rev Mol Cell Biol. 2008 ;9:139-150.
8. Morad SA, Cabot MC. Ceramide-orchestrated signalling in cancer cells. Nat Rev Cancer. 2013; 13:51-65.
9. Truman JP, García-Barros M, Obeid LM, Hannun YA. Evolving concepts in cancer therapy through targeting sphingolipid metabolism. Biochim Biophys Acta. 2014; 1841:1174-1188.
10. Ponnusamy S, Meyers-Needham M, Senkal CE, Saddoughi SA, Sentelle D, Selvam SP, Salas A, Ogretmen B. Sphingolipids and cancer: ceramide and sphingosine-1-phosphate in the regulation of cell death and drug resistance. Future Oncol. 2010; 6:1603-1624.
11. Senchenkov A, Litvak DA, Cabot MC. Targeting ceramide metabolism--a strategy for overcoming drug resistance. J Natl Cancer Inst. 2001; 93:347-357.
12. Tagaram HR, Divittore NA, Barth BM, Kaiser JM, Avella D, Kimchi ET, Jiang Y, Isom HC, Kester M, Staveley-O'Carroll KF. Nanoliposomal ceramide prevents in vivo growth of hepatocellular carcinoma. Gut. 2011; 60:695-701.
13. Morales A, París R, Villanueva A, Llacuna L, García-Ruiz C, Fernández-Checa JC. Pharmacological inhibition or small interfering RNA targeting acid ceramidase sensitizes hepatoma cells to chemotherapy and reduces tumor growth in vivo. Oncogene. 2007; 26:905-916.
14. Savić R, He X, Fiel I, Schuchman EH. Recombinant human acid sphingomyelinase as an adjuvant to sorafenib treatment of experimental liver cancer. PLoS One. 2013; 8:e65620.
15. Tran MA, Smith CD, Kester M, Robertson GP. Combining nanoliposomal ceramide with sorafenib synergistically inhibits melanoma and breast cancer cell survival to decrease tumor development. Clin Cancer Res. 2008; 14:3571-3581.
16. Morales A, Mari M, Garcia-Ruiz C, Colell A, Fernandez-Checa JC. Hepatocarcinogenesis and ceramide/cholesterol metabolism. Anticancer Agents Med Chem. 2012; 12:364-375.
17. Marí M, Caballero F, Colell A, Morales A, Caballeria J, Fernandez A, Enrich C, Fernandez-Checa JC, García-Ruiz C. Mitochondrial free cholesterol loading sensitizes to TNF- and Fas-mediated steatohepatitis. Cell Metab. 2006; 4:185-198.
18. Llacuna L, Marí M, Garcia-Ruiz C, Fernandez-Checa JC, Morales A. Critical role of acidic sphingomyelinase in murine hepatic ischemia-reperfusion injury. Hepatology. 2006; 44:561-572.
19. Montero J, Morales A, Llacuna L, Lluis JM, Terrones O, Basañez G, Antonsson B, Prieto J, García-Ruiz C, Colell A, Fernández-Checa JC. Mitochondrial cholesterol contributes to chemotherapy resistance in hepatocellular carcinoma. Cancer Res. 2008; 68:5246-5256.
20. Kolesnick R. The therapeutic potential of modulating the ceramide/sphingomyelin pathway. J Clin Invest. 2002; 110:3-8.
21. Levy M, Futerman AH. Mammalian ceramide synthases. IUBMB Life. 2010; 62:347-356.
22. Morales A, Fernandez-Checa JC. Pharmacological modulation of sphingolipids and role in disease and cancer cell biology. Mini Rev Med Chem. 2007; 7:371-382.
23. Panka DJ, Wang W, Atkins MB, Mier JW. The Raf inhibitor BAY 43-9006 (Sorafenib) induces caspase-independent apoptosis in melanoma cells. Cancer Res. 2006; 66:1611-1619.
24. Sentelle RD, Senkal CE, Jiang W, Ponnusamy S, Gencer S, Selvam SP, Ramshesh VK, Peterson YK, Lemasters JJ, Szulc ZM, Bielawski J, Ogretmen B. Ceramide targets autophagosomes to mitochondria and induces lethal mitophagy. Nat Chem Biol. 2012; 8:831-838.
25. Zhai B, Hu F, Jiang X, Xu J, Zhao D, Liu B, Pan S, Dong X, Tan G, Wei Z, Qiao H, Jiang H, Sun X. Inhibition of Akt reverses the acquired resistance to sorafenib by switching protective autophagy to autophagic cell death in hepatocellular carcinoma. Mol Cancer Ther. 2014; 13:1589-1598.
26. Pattingre S, Tassa A, Qu X, Garuti R, Liang XH, Mizushima N, Packer M, Schneider MD, Levine B. Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell. 2005; 122:927-939.
27. Tai WT1, Shiau CW, Chen HL, Liu CY, Lin CS, Cheng AL, Chen PJ, Chen KF. Mcl-1-dependent activation of Beclin 1 mediates autophagic cell death induced by sorafenib and SC-59 in hepatocellular carcinoma cells. Cell Death Dis. 2013; 4:e485.
28. Colell A, Ricci JE, Tait S, Milasta S, Maurer U, Bouchier-Hayes L, Fitzgerald P, Guio-Carrion A, Waterhouse NJ, Li CW, Mari B, Barbry P, Newmeyer DD, et al. GAPDH and autophagy preserve survival after apoptotic cytochrome c release in the absence of caspase activation. Cell. 2007; 129:983-997.
29. Shen W, Henry AG, Paumier KL, Li L, Mou K, Dunlop J, Berger Z, Hirst WD. Inhibition of glucosylceramide synthase stimulates autophagy flux in neurons. J Neurochem. 2014; 129:884-894.
30. Bull VH, Rajalingam K, Thiede B. Sorafenib-induced mitochondrial complex I inactivation and cell death in human neuroblastoma cells. J Proteome Res. 2012; 11:1609-1620.
31. García-Ruiz C, Colell A, Marí M, Morales A, Fernández-Checa JC. Direct effect of ceramide on the mitochondrial electron transport chain leads to generation of reactive oxygen species. Role of mitochondrial glutathione. J Biol Chem. 1997; 272:11369-11377.
32. Chipuk JE, McStay GP, Bharti A, Kuwana T, Clarke CJ, Siskind LJ, Obeid LM, Green DR. Sphingolipid metabolism cooperates with BAK and BAX to promote the mitochondrial pathway of apoptosis. Cell. 2012; 148:988-1000.
33. Lee H, Rotolo JA, Mesicek J, Penate-Medina T, Rimner A, Liao WC, Yin X, Ragupathi G, Ehleiter D, Gulbins E, Zhai D, Reed JC, Haimovitz-Friedman A, et al. Mitochondrial ceramide-rich macrodomains functionalize Bax upon irradiation. PLoS One. 2011; 6:e19783.
34. Tait SW, Ichim G, Green DR. Die another way--non-apoptotic mechanisms of cell death. J Cell Sci. 2014; 127:2135-2144.
35. Phillips NR1, Sprouse ML1, Roby RK2. Simultaneous quantification of mitochondrial DNA copy number and deletion ratio: a multiplex real-time PCR assay. Sci Rep. 2014; 4:3887.
36. Ryland LK, Doshi UA, Shanmugavelandy SS, Fox TE, Aliaga C, Broeg K, Baab KT, Young M, Khan O, Haakenson JK, Jarbadan NR, Liao J, Wang HG, et al. C6-ceramide nanoliposomes target the Warburg effect in chronic lymphocytic leukemia. PLoS One. 2013; 8:e84648.
37. Chow AK, Ng L, Lam CS, Wong SK, Wan TM, Cheng NS, Yau TC, Poon RT, Pang RW. The enhanced metastatic potential of hepatocellular carcinoma (HCC) cells with sorafenib resistance. PLoS One. 2013; 8:e78675.
38. Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, Chen C, Zhang X, Vincent P, McHugh M, Cao Y, Shujath J, Gawlak S, et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004; 64:7099-7109.
39. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008; 359:378-390.
40. Huang WC, Tsai CC, Chen CL, Chen TY, Chen YP, Lin YS, Lu PJ, Lin CM, Wang SH, Tsao CW, Wang CY, Cheng YL, Hsieh CY, et al. Glucosylceramide synthase inhibitor PDMP sensitizes chronic myeloid leukemia T315I mutant to Bcr-Abl inhibitor and cooperatively induces glycogen synthase kinase-3-regulated apoptosis. FASEB J. 2011; 25:3661-673.
41. Shayman JA. Eliglustat tartrate: Glucosylceramide Synthase Inhibitor Treatment of Type 1 Gaucher Disease. Drugs Future. 2010; 35:613-620.
42. Poole RM. Eliglustat: first global approval. Drugs. 2014; 74:1829-1836.
43. Tait SW, Parsons MJ, Llambi F, Bouchier-Hayes L, Connell S, Muñoz-Pinedo C, Green DR. Resistance to caspase-independent cell death requires persistence of intact mitochondria. Dev Cell. 2010; 18:802-813.
44. Tesori V, Piscaglia AC, Samengo D, Barba M, Bernardini C, Scatena R, Pontoglio A, Castellini L, Spelbrink JN, Maulucci G, Puglisi MA, Pani G, Gasbarrini A. The multikinase inhibitor Sorafenib enhances glycolysis and synergizes with glycolysis blockade for cancer cell killing. Sci Rep. 2015; 5:9149.
45. Hikita H, Takehara T, Shimizu S, Kodama T, Shigekawa M, Iwase K, Hosui A, Miyagi T, Tatsumi T, Ishida H, Li W, Kanto T, Hiramatsu N, et al. The Bcl-xL inhibitor, ABT-737, efficiently induces apoptosis and suppresses growth of hepatoma cells in combination with sorafenib. Hepatology. 2010; 52:1310-1321.
46. Chiu WH, Su WC, Li CL, Chen CL, Lin CF. An increase in glucosylceramide synthase induces Bcl-xL-mediated cell survival in vinorelbine-resistant lung adenocarcinoma cells. Oncotarget. 2015; 6:20513-24. doi: 10.18632/oncotarget.4109.
47. Beverly LJ1, Howell LA, Hernandez-Corbacho M, Casson L, Chipuk JE, Siskind LJ. BAK activation is necessary and sufficient to drive ceramide synthase-dependent ceramide accumulation following inhibition of BCL2-like proteins. Biochem J. 2013; 452:111-119.
48. Lamb R, Ozsvari B, Lisanti CL, Tanowitz HB, Howell A, Martinez-Outschoorn UE, Sotgia F, Lisanti MP. Antibiotics that target mitochondria effectively eradicate cancer stem cells, across multiple tumor types: treating cancer like an infectious disease. Oncotarget. 2015; 6:4569-84. doi: 10.18632/oncotarget.3174.