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Open Access 01-12-2010 | Research

Glucosylceramide synthase upregulates MDR1 expression in the regulation of cancer drug resistance through cSrc and β-catenin signaling

Authors: Yong-Yu Liu, Vineet Gupta, Gauri A Patwardhan, Kaustubh Bhinge, Yunfeng Zhao, Jianxiong Bao, Harihara Mehendale, Myles C Cabot, Yu-Teh Li, S Michal Jazwinski

Published in: Molecular Cancer | Issue 1/2010

Abstract

Background

Drug resistance is the outcome of multiple-gene interactions in cancer cells under stress of anticancer agents. MDR1 overexpression is most commonly detected in drug-resistant cancers and accompanied with other gene alterations including enhanced glucosylceramide synthase (GCS). MDR1 encodes for P-glycoprotein that extrudes anticancer drugs. Polymorphisms of MDR1 disrupt the effects of P-glycoprotein antagonists and limit the success of drug resistance reversal in clinical trials. GCS converts ceramide to glucosylceramide, reducing the impact of ceramide-induced apoptosis and increasing glycosphingolipid (GSL) synthesis. Understanding the molecular mechanisms underlying MDR1 overexpression and how it interacts with GCS may find effective approaches to reverse drug resistance.

Results

MDR1 and GCS were coincidently overexpressed in drug-resistant breast, ovary, cervical and colon cancer cells; silencing GCS using a novel mixed-backbone oligonucleotide (MBO-asGCS) sensitized these four drug-resistant cell lines to doxorubicin. This sensitization was correlated with the decreased MDR1 expression and the increased doxorubicin accumulation. Doxorubicin treatment induced GCS and MDR1 expression in tumors, but MBO-asGCS treatment eliminated "in-vivo" growth of drug-resistant tumor (NCI/ADR-RES). MBO-asGCS suppressed the expression of MDR1 with GCS and sensitized NCI/ADR-RES tumor to doxorubicin. The expression of P-glycoprotein and the function of its drug efflux of tumors were decreased by 4 and 8 times after MBO-asGCS treatment, even though this treatment did not have a significant effect on P-glycoprotein in normal small intestine. GCS transient transfection induced MDR1 overexpression and increased P-glycoprotein efflux in dose-dependent fashion in OVCAR-8 cancer cells. GSL profiling, silencing of globotriaosylceramide synthase and assessment of signaling pathway indicated that GCS transfection significantly increased globo series GSLs (globotriaosylceramide Gb3, globotetraosylceramide Gb4) on GSL-enriched microdomain (GEM), activated cSrc kinase, decreased β-catenin phosphorylation, and increased nuclear β-catenin. These consequently increased MDR1 promoter activation and its expression. Conversely, MBO-asGCS treatments decreased globo series GSLs (Gb3, Gb4), cSrc kinase and nuclear β-catenin, and suppressed MDR-1 expression in dose-dependent pattern.

Conclusion

This study demonstrates, for the first time, that GCS upregulates MDR1 expression modulating drug resistance of cancer. GSLs, in particular globo series GSLs mediate gene expression of MDR1 through cSrc and β-catenin signaling pathway.

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Harris AL, Hochhauser D: Mechanisms of multidrug resistance in cancer treatment. Acta Oncol. 1992, 31: 205-213. 10.3109/02841869209088904CrossRefPubMed

Gottesman MM: Mechanisms of cancer drug resistance. Annu Rev Med. 2002, 53: 615-627. 10.1146/annurev.med.53.082901.103929CrossRefPubMed

Kimura Y, Morita SY, Matsuo M, Ueda K: Mechanism of multidrug recognition by MDR1/ABCB1. Cancer Sci. 2007, 98: 1303-1310. 10.1111/j.1349-7006.2007.00538.xCrossRefPubMed

Ambudkar SV, Kimchi-Sarfaty C, Sauna ZE, Gottesman MM: P-glycoprotein: from genomics to mechanism. Oncogene. 2003, 22: 7468-7485. 10.1038/sj.onc.1206948CrossRefPubMed

Ahmed FE: Molecular markers that predict response to colon cancer therapy. Expert Rev Mol Diagn. 2005, 5: 353-375. 10.1586/14737159.5.3.353CrossRefPubMed

Sarkadi B, Muller M, Hollo Z: The multidrug transporters--proteins of an ancient immune system. Immunol Lett. 1996, 54: 215-219. 10.1016/S0165-2478(96)02676-4CrossRefPubMed

Kimchi-Sarfaty C, Oh JM, Kim IW, Sauna ZE, Calcagno AM, Ambudkar SV, Gottesman MM: A "silent" polymorphism in the MDR1 gene changes substrate specificity. Science. 2007, 315: 525-528. 10.1126/science.1135308CrossRefPubMed

Mahadevan D, List AF: Targeting the multidrug resistance-1 transporter in AML: molecular regulation and therapeutic strategies. Blood. 2004, 104: 1940-1951. 10.1182/blood-2003-07-2490CrossRefPubMed

McDevitt CA, Callaghan R: How can we best use structural information on P-glycoprotein to design inhibitors?. Pharmacol Ther. 2007, 113: 429-441. 10.1016/j.pharmthera.2006.10.003CrossRefPubMed

10.

Leonard GD, Polgar O, Bates SE: ABC transporters and inhibitors: new targets, new agents. Curr Opin Investig Drugs. 2002, 3: 1652-1659.PubMed

11.

el-Deiry WS: Role of oncogenes in resistance and killing by cancer therapeutic agents. Curr Opin Oncol. 1997, 9: 79-87. 10.1097/00001622-199701000-00013CrossRefPubMed

12.

Wojtal KA, de Vries E, Hoekstra D, van Ijzendoorn SC: Efficient trafficking of MDR1/P-glycoprotein to apical canalicular plasma membranes in HepG2 cells requires PKA-RIIalpha anchoring and glucosylceramide. Mol Biol Cell. 2006, 17: 3638-3650. 10.1091/mbc.E06-03-0230PubMedCentralCrossRefPubMed

13.

Liu YY, Han TY, Giuliano AE, Cabot MC: Ceramide glycosylation potentiates cellular multidrug resistance. FASEB J. 2001, 15: 719-730. 10.1096/fj.00-0223comCrossRefPubMed

14.

Reynolds CP, Maurer BJ, Kolesnick RN: Ceramide synthesis and metabolism as a target for cancer therapy. Cancer Lett. 2004, 206: 169-180. 10.1016/j.canlet.2003.08.034CrossRefPubMed

15.

Senchenkov A, Litvak DA, Cabot MC: Targeting ceramide metabolism--a strategy for overcoming drug resistance. J Natl Cancer Inst. 2001, 93: 347-357. 10.1093/jnci/93.5.347CrossRefPubMed

16.

Liu YY, Han TY, Giuliano AE, Cabot MC: Expression of glucosylceramide synthase, converting ceramide to glucosylceramide, confers adriamycin resistance in human breast cancer cells. J Biol Chem. 1999, 274: 1140-1146. 10.1074/jbc.274.2.1140CrossRefPubMed

17.

Liu YY, Yu JY, Yin D, Patwardhan GA, Gupta V, Hirabayashi Y, Holleran WM, Giuliano AE, Jazwinski SM, Gouaze-Andersson V: A role for ceramide in driving cancer cell resistance to doxorubicin. FASEB J. 2008, 22: 2541-2551. 10.1096/fj.07-092981CrossRefPubMed

18.

Gouaze V, Liu YY, Prickett CS, Yu JY, Giuliano AE, Cabot MC: Glucosylceramide synthase blockade down-regulates P-glycoprotein and resensitizes multidrug-resistant breast cancer cells to anticancer drugs. Cancer Res. 2005, 65: 3861-3867. 10.1158/0008-5472.CAN-04-2329CrossRefPubMed

19.

Hannun YA: The sphingomyelin cycle and the second messenger function of ceramide. J Biol Chem. 1994, 269: 3125-3128.PubMed

20.

Ichikawa S, Hirabayashi Y: Glucosylceramide synthase and glycosphingolipid synthesis. Trends Cell Biol. 1998, 8: 198-202. 10.1016/S0962-8924(98)01249-5CrossRefPubMed

21.

Yamashita T, Wada R, Sasaki T, Deng C, Bierfreund U, Sandhoff K, Proia RL: A vital role for glycosphingolipid synthesis during development and differentiation. Proc Natl Acad Sci USA. 1999, 96: 9142-9147. 10.1073/pnas.96.16.9142PubMedCentralCrossRefPubMed

22.

Kolesnick R, Altieri D, Fuks Z: A CERTain role for ceramide in taxane-induced cell death. Cancer Cell. 2007, 11: 473-475. 10.1016/j.ccr.2007.05.003CrossRefPubMed

23.

Kolesnick R, Hannun YA: Ceramide and apoptosis. Trends Biochem Sci. 1999, 24: 224-225. 10.1016/S0968-0004(99)01408-5CrossRefPubMed

24.

Ogretmen B, Hannun YA: Updates on functions of ceramide in chemotherapy-induced cell death and in multidrug resistance. Drug Resist Updat. 2001, 4: 368-377. 10.1054/drup.2001.0225CrossRefPubMed

25.

Kolesnick R, Fuks Z: Radiation and ceramide-induced apoptosis. Oncogene. 2003, 22: 5897-5906. 10.1038/sj.onc.1206702CrossRefPubMed

26.

Ogretmen B, Schady D, Usta J, Wood R, Kraveka JM, Luberto C, Birbes H, Hannun YA, Obeid LM: Role of ceramide in mediating the inhibition of telomerase activity in A549 human lung adenocarcinoma cells. J Biol Chem. 2001, 276: 24901-24910. 10.1074/jbc.M100314200CrossRefPubMed

27.

Liu YY, Han TY, Giuliano AE, Ichikawa S, Hirabayashi Y, Cabot MC: Glycosylation of ceramide potentiates cellular resistance to tumor necrosis factor-alpha-induced apoptosis. Exp Cell Res. 1999, 252: 464-470. 10.1006/excr.1999.4649CrossRefPubMed

28.

Gouaze V, Yu JY, Bleicher RJ, Han TY, Liu YY, Wang H, Gottesman MM, Bitterman A, Giuliano AE, Cabot MC: Overexpression of glucosylceramide synthase and P-glycoprotein in cancer cells selected for resistance to natural product chemotherapy. Mol Cancer Ther. 2004, 3: 633-639.PubMed

29.

Jones J, Otu H, Spentzos D, Kolia S, Inan M, Beecken WD, Fellbaum C, Gu X, Joseph M, Pantuck AJ: Gene signatures of progression and metastasis in renal cell cancer. Clin Cancer Res. 2005, 11: 5730-5739. 10.1158/1078-0432.CCR-04-2225CrossRefPubMed

30.

Ruckhaberle E, Karn T, Hanker L, Gatje R, Metzler D, Holtrich U, Kaufmann M, Rody A: Prognostic relevance of glucosylceramide synthase (GCS) expression in breast cancer. J Cancer Res Clin Oncol. 2009, 135: 81-90. 10.1007/s00432-008-0436-9CrossRefPubMed

31.

Itoh M, Kitano T, Watanabe M, Kondo T, Yabu T, Taguchi Y, Iwai K, Tashima M, Uchiyama T, Okazaki T: Possible role of ceramide as an indicator of chemoresistance: decrease of the ceramide content via activation of glucosylceramide synthase and sphingomyelin synthase in chemoresistant leukemia. Clin Cancer Res. 2003, 9: 415-423.PubMed

32.

Shabbits JA, Mayer LD: P-glycoprotein modulates ceramide-mediated sensitivity of human breast cancer cells to tubulin-binding anticancer drugs. Mol Cancer Ther. 2002, 1: 205-213.PubMed

33.

Xie P, Shen YF, Shi YP, Ge SM, Gu ZH, Wang J, Mu HJ, Zhang B, Qiao WZ, Xie KM: Overexpression of glucosylceramide synthase in associated with multidrug resistance of leukemia cells. Leuk Res. 2008, 32: 475-480. 10.1016/j.leukres.2007.07.006CrossRefPubMed

34.

Liu YY, Han TY, Yu JY, Bitterman A, Le A, Giuliano AE, Cabot MC: Oligonucleotides blocking glucosylceramide synthase expression selectively reverse drug resistance in cancer cells. J Lipid Res. 2004, 45: 933-940. 10.1194/jlr.M300486-JLR200CrossRefPubMed

35.

Patwardhan GA, Zhang QJ, Yin D, Gupta V, Bao J, Senkal CE, Ogretmen B, Cabot MC, Shah GV, Sylvester PW: A new mixed-backbone oligonucleotide against glucosylceramide synthase Sensitizes multidrug-resistant tumors to apoptosis. PLoS One. 2009, 4: e6938- 10.1371/journal.pone.0006938PubMedCentralCrossRefPubMed

36.

Brimacombe KR, Hall MD, Auld DS, Inglese J, Austin CP, Gottesman MM, Fung KL: A dual-fluorescence high-throughput cell line system for probing multidrug resistance. Assay Drug Dev Technol. 2009, 7: 233-249. 10.1089/adt.2008.165PubMedCentralCrossRefPubMed

37.

Maupas-Schwalm F, Robinet C, Auge N, Thiers JC, Garcia V, Cambus JP, Salvayre R, Negre-Salvayre A: Activation of the {beta}-catenin/T-cell-specific transcription factor/lymphoid enhancer factor-1 pathway by plasminogen activators in ECV304 carcinoma cells. Cancer Res. 2005, 65: 526-532.PubMed

38.

Chen JK, Capdevila J, Harris RC: Overexpression of C-terminal Src kinase blocks 14, 15-epoxyeicosatrienoic acid-induced tyrosine phosphorylation and mitogenesis. J Biol Chem. 2000, 275: 13789-13792. 10.1074/jbc.275.18.13789CrossRefPubMed

39.

Steelant WF, Kawakami Y, Ito A, Handa K, Bruyneel EA, Mareel M, Hakomori S: Monosialyl-Gb5 organized with cSrc and FAK in GEM of human breast carcinoma MCF-7 cells defines their invasive properties. FEBS Lett. 2002, 531: 93-98. 10.1016/S0014-5793(02)03484-1CrossRefPubMed

40.

Van Slambrouck S, Steelant WF: Clustering of monosialyl-Gb5 initiates downstream signalling events leading to invasion of MCF-7 breast cancer cells. Biochem J. 2007, 401: 689-699. 10.1042/BJ20060944PubMedCentralCrossRefPubMed

41.

Hitosugi T, Sato M, Sasaki K, Umezawa Y: Lipid raft specific knockdown of SRC family kinase activity inhibits cell adhesion and cell cycle progression of breast cancer cells. Cancer Res. 2007, 67: 8139-8148. 10.1158/0008-5472.CAN-06-4539CrossRefPubMed

42.

Arab S, Murakami M, Dirks P, Boyd B, Hubbard SL, Lingwood CA, Rutka JT: Verotoxins inhibit the growth of and induce apoptosis in human astrocytoma cells. J Neurooncol. 1998, 40: 137-150. 10.1023/A:1006010019064CrossRefPubMed

43.

Kiarash A, Boyd B, Lingwood CA: Glycosphingolipid receptor function is modified by fatty acid content. Verotoxin 1 and verotoxin 2c preferentially recognize different globotriaosyl ceramide fatty acid homologues. J Biol Chem. 1994, 269: 11138-11146.PubMed

44.

Lala P, Ito S, Lingwood CA: Retroviral transfection of Madin-Darby canine kidney cells with human MDR1 results in a major increase in globotriaosylceramide and 10(5)- to 10(6)-fold increased cell sensitivity to verocytotoxin. Role of p-glycoprotein in glycolipid synthesis. J Biol Chem. 2000, 275: 6246-6251. 10.1074/jbc.275.9.6246CrossRefPubMed

45.

Handeli S, Simon JA: A small-molecule inhibitor of Tcf/beta-catenin signaling down-regulates PPARgamma and PPARdelta activities. Mol Cancer Ther. 2008, 7: 521-529. 10.1158/1535-7163.MCT-07-2063CrossRefPubMed

46.

Gerrard G, Butters TD, Ganeshaguru K, Mehta AB: Glucosylceramide synthase inhibitors sensitise CLL cells to cytotoxic agents without reversing P-gp functional activity. Eur J Pharmacol. 2009, 609: 34-39. 10.1016/j.ejphar.2009.03.018CrossRefPubMed

47.

De Rosa MF, Sillence D, Ackerley C, Lingwood C: Role of multiple drug resistance protein 1 in neutral but not acidic glycosphingolipid biosynthesis. J Biol Chem. 2004, 279: 7867-7876. 10.1074/jbc.M305645200CrossRefPubMed

48.

Morjani H, Aouali N, Belhoussine R, Veldman RJ, Levade T, Manfait M: Elevation of glucosylceramide in multidrug-resistant cancer cells and accumulation in cytoplasmic droplets. Int J Cancer. 2001, 94: 157-165. 10.1002/ijc.1449CrossRefPubMed

49.

Madden MJ, Morrow CS, Nakagawa M, Goldsmith ME, Fairchild CR, Cowan KH: Identification of 5' and 3' sequences involved in the regulation of transcription of the human mdr1 gene in vivo. J Biol Chem. 1993, 268: 8290-8297.PubMed

50.

Tetsu O, McCormick F: Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature. 1999, 398: 422-426. 10.1038/18884CrossRefPubMed

51.

Yamada T, Takaoka AS, Naishiro Y, Hayashi R, Maruyama K, Maesawa C, Ochiai A, Hirohashi S: Transactivation of the multidrug resistance 1 gene by T-cell factor 4/beta-catenin complex in early colorectal carcinogenesis. Cancer Res. 2000, 60: 4761-4766.PubMed

52.

Yamada T, Mori Y, Hayashi R, Takada M, Ino Y, Naishiro Y, Kondo T, Hirohashi S: Suppression of intestinal polyposis in Mdr1-deficient ApcMin/+ mice. Cancer Res. 2003, 63: 895-901.PubMed

53.

Lim JC, Kania KD, Wijesuriya H, Chawla S, Sethi JK, Pulaski L, Romero IA, Couraud PO, Weksler BB, Hladky SB, Barrand MA: Activation of beta-catenin signalling by GSK-3 inhibition increases p-glycoprotein expression in brain endothelial cells. J Neurochem. 2008, 106: 1855-1865.PubMedCentralPubMed

54.

Karni R, Gus Y, Dor Y, Meyuhas O, Levitzki A: Active Src elevates the expression of beta-catenin by enhancement of cap-dependent translation. Mol Cell Biol. 2005, 25: 5031-5039. 10.1128/MCB.25.12.5031-5039.2005PubMedCentralCrossRefPubMed

55.

Chang YM, Bai L, Liu S, Yang JC, Kung HJ, Evans CP: Src family kinase oncogenic potential and pathways in prostate cancer as revealed by AZD0530. Oncogene. 2008, 27: 6365-6375. 10.1038/onc.2008.250PubMedCentralCrossRefPubMed

56.

Kazui A, Ono M, Handa K, Hakomori S: Glycosylation affects translocation of integrin, Src, and caveolin into or out of GEM. Biochem Biophys Res Commun. 2000, 273: 159-163. 10.1006/bbrc.2000.2903CrossRefPubMed

57.

Hakomori Si SI: Inaugural Article: The glycosynapse. Proc Natl Acad Sci USA. 2002, 99: 225-232. 10.1073/pnas.012540899PubMedCentralCrossRefPubMed

58.

Katagiri YU, Mori T, Nakajima H, Katagiri C, Taguchi T, Takeda T, Kiyokawa N, Fujimoto J: Activation of Src family kinase yes induced by Shiga toxin binding to globotriaosyl ceramide (Gb3/CD77) in low density, detergent-insoluble microdomains. J Biol Chem. 1999, 274: 35278-35282. 10.1074/jbc.274.49.35278CrossRefPubMed

59.

Malyukova I, Murray KF, Zhu C, Boedeker E, Kane A, Patterson K, Peterson JR, Donowitz M, Kovbasnjuk O: Macropinocytosis in Shiga toxin 1 uptake by human intestinal epithelial cells and transcellular transcytosis. Am J Physiol Gastrointest Liver Physiol. 2009, 296: G78-92. 10.1152/ajpgi.90347.2008PubMedCentralCrossRefPubMed

60.

Mori T, Kiyokawa N, Katagiri YU, Taguchi T, Suzuki T, Sekino T, Sato N, Ohmi K, Nakajima H, Takeda T, Fujimoto J: Globotriaosyl ceramide (CD77/Gb3) in the glycolipid-enriched membrane domain participates in B-cell receptor-mediated apoptosis by regulating lyn kinase activity in human B cells. Exp Hematol. 2000, 28: 1260-1268. 10.1016/S0301-472X(00)00538-5CrossRefPubMed

61.

De Rosa MF, Ackerley C, Wang B, Ito S, Clarke DM, Lingwood C: Inhibition of multidrug resistance by adamantylgb3, a globotriaosylceramide analog. J Biol Chem. 2008, 283: 4501-4511. 10.1074/jbc.M705473200CrossRefPubMed

62.

Inokuchi JI, Uemura S, Kabayama K, Igarashi Y: Glycosphingolipid deficiency affects functional microdomain formation in Lewis lung carcinoma cells. Glycoconj J. 2000, 17: 239-245. 10.1023/A:1026549525628CrossRefPubMed

63.

Fairchild CR, Ivy SP, Kao-Shan CS, Whang-Peng J, Rosen N, Israel MA, Melera PW, Cowan KH, Goldsmith ME: Isolation of amplified and overexpressed DNA sequences from adriamycin-resistant human breast cancer cells. Cancer Res. 1987, 47: 5141-5148.PubMed

64.

Mehta K, Devarajan E, Chen J, Multani A, Pathak S: Multidrug-resistant MCF-7 cells: an identity crisis?. J Natl Cancer Inst. 2002, 94: 1652-1654.CrossRefPubMed

65.

Rogan AM, Hamilton TC, Young RC, Klecker RW, Ozols RF: Reversal of adriamycin resistance by verapamil in human ovarian cancer. Science. 1984, 224: 994-996. 10.1126/science.6372095CrossRefPubMed

66.

Akiyama S, Fojo A, Hanover JA, Pastan I, Gottesman MM: Isolation and genetic characterization of human KB cell lines resistant to multiple drugs. Somat Cell Mol Genet. 1985, 11: 117-126. 10.1007/BF01534700CrossRefPubMed

67.

Lai GM, Chen YN, Mickley LA, Fojo AT, Bates SE: P-glycoprotein expression and schedule dependence of adriamycin cytotoxicity in human colon carcinoma cell lines. Int J Cancer. 1991, 49: 696-703. 10.1002/ijc.2910490512CrossRefPubMed

68.

Primeau AJ, Rendon A, Hedley D, Lilge L, Tannock IF: The distribution of the anticancer drug Doxorubicin in relation to blood vessels in solid tumors. Clin Cancer Res. 2005, 11: 8782-8788. 10.1158/1078-0432.CCR-05-1664CrossRefPubMed

69.

Mistry P, Stewart AJ, Dangerfield W, Okiji S, Liddle C, Bootle D, Plumb JA, Templeton D, Charlton P: In vitro and in vivo reversal of P-glycoprotein-mediated multidrug resistance by a novel potent modulator, XR9576. Cancer Res. 2001, 61: 749-758.PubMed

70.

Liu YY, Han TY, Giuliano AE, Hansen N, Cabot MC: Uncoupling ceramide glycosylation by transfection of glucosylceramide synthase antisense reverses adriamycin resistance. J Biol Chem. 2000, 275: 7138-7143. 10.1074/jbc.275.10.7138CrossRefPubMed

71.

Ichikawa S, Sakiyama H, Suzuki G, Hidari KI, Hirabayashi Y: Expression cloning of a cDNA for human ceramide glucosyltransferase that catalyzes the first glycosylation step of glycosphingolipid synthesis. Proc Natl Acad Sci USA. 1996, 93: 4638-4643. 10.1073/pnas.93.10.4638PubMedCentralCrossRefPubMed

72.

Klenova E, Chernukhin I, Inoue T, Shamsuddin S, Norton J: Immunoprecipitation techniques for the analysis of transcription factor complexes. Methods. 2002, 26: 254-259. 10.1016/S1046-2023(02)00029-4CrossRefPubMed

73.

Gupta V, Patwardhan GA, Zhang QJ, Cabot MC, Jazwinski SM, Liu YY: Direct quantitative determination of ceramide glycosylation in vivo: a new approach to evaluate cellular enzyme activity of glucosylceramide synthase. J Lipid Res. 2010, 51: 866-874. 10.1194/jlr.D002949PubMedCentralCrossRefPubMed

74.

Anderson K, Li SC, Li YT: Diphenylamine-aniline-phosphoric acid reagent, a versatile spray reagent for revealing glycoconjugates on thin-layer chromatography plates. Anal Biochem. 2000, 287: 337-339. 10.1006/abio.2000.4829CrossRefPubMed

75.

Rodgers W, Rose JK: Exclusion of CD45 inhibits activity of p56lck associated with glycolipid-enriched membrane domains. J Cell Biol. 1996, 135: 1515-1523. 10.1083/jcb.135.6.1515CrossRefPubMed

76.

Zhou Q, Chowbay B: Determination of doxorubicin and its metabolites in rat serum and bile by LC: application to preclinical pharmacokinetic studies. J Pharm Biomed Anal. 2002, 30: 1063-1074. 10.1016/S0731-7085(02)00442-9CrossRefPubMed

77.

Mitra MS, Donthamsetty S, White B, Latendresse JR, Mehendale HM: Mechanism of protection of moderately diet restricted rats against doxorubicin-induced acute cardiotoxicity. Toxicol Appl Pharmacol. 2007, 225: 90-101. 10.1016/j.taap.2007.07.018CrossRefPubMed

78.

Diaz JF, Strobe R, Engelborghs Y, Souto AA, Andreu JM: Molecular recognition of taxol by microtubules. Kinetics and thermodynamics of binding of fluorescent taxol derivatives to an exposed site. J Biol Chem. 2000, 275: 26265-26276. 10.1074/jbc.M003120200CrossRefPubMed

79.

Patwardhan G, Gupta V, Huang J, Gu X, Liu YY: Direct assessment of P-glycoprotein efflux to determine tumor response to chemotherapy. Biochem Pharmacol. 2010, 80: 72-79. 10.1016/j.bcp.2010.03.010PubMedCentralCrossRefPubMed

80.

Bogin L, Degani H: Hormonal regulation of VEGF in orthotopic MCF-7 human breast cancer. Cancer Res. 2002, 62: 1948-1951.PubMed

81.

Jin S, Scotto KW: Transcriptional regulation of the MDR1 gene by histone acetyltransferase and deacetylase is mediated by NF-Y. Mol Cell Biol. 1998, 18: 4377-4384.PubMedCentralCrossRefPubMed

Title: Glucosylceramide synthase upregulates MDR1 expression in the regulation of cancer drug resistance through cSrc and β-catenin signaling
Authors: Yong-Yu Liu
Vineet Gupta
Gauri A Patwardhan
Kaustubh Bhinge
Yunfeng Zhao
Jianxiong Bao
Harihara Mehendale
Myles C Cabot
Yu-Teh Li
S Michal Jazwinski
Publication date: 01-12-2010
Publisher: BioMed Central
Published in: Molecular Cancer / Issue 1/2010
Electronic ISSN: 1476-4598
DOI: https://doi.org/10.1186/1476-4598-9-145

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