期刊论文详细信息
BMC Cancer
Lipid metabolism enzyme ACSVL3 supports glioblastoma stem cell maintenance and tumorigenicity
Peng Sun4  Shuli Xia3  Bachchu Lal2  Xiaohai Shi2  Kil Sung Yang2  Paul A Watkins3  John Laterra1 
[1] Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, USA
[2] Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, MD, USA
[3] Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA
[4] MD Anderson Cancer Center, Houston, TX, USA
关键词: Tumorigenicity;    Differentiation;    Cancer stem cell;    Glioblastoma;    ACSVL3;    Lipid metabolism;   
Others  :  858720
DOI  :  10.1186/1471-2407-14-401
 received in 2013-10-02, accepted in 2014-05-21,  发布年份 2014
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【 摘 要 】

Background

Targeting cell metabolism offers promising opportunities for the development of drugs to treat cancer. We previously found that the fatty acyl-CoA synthetase VL3 (ACSVL3) is elevated in malignant brain tumor tissues and involved in tumorigenesis. This study investigates the role of ACSVL3 in the maintenance of glioblastoma multiforme (GBM) stem cell self-renewal and the capacity of GBM stem cells to initiate tumor xenograft formation.

Methods

We examined ACSVL3 expression during differentiation of several GBM stem cell enriched neurosphere cultures. To study the function of ACSVL3, we performed loss-of-function by using small interfering RNAs to target ACSVL3 and examined stem cell marker expression, neurosphere formation and tumor initiation properties.

Results

ACSVL3 expression levels were substantially increased in GBM stem cell enriched neurosphere cultures and decreased after differentiation of the neurospheres. Down-regulating ACSVL3 with small inhibiting RNAs decreased the expression of markers and regulators associated with stem cell self-renewal, including CD133, ALDH, Musashi-1 and Sox-2. ACSVL3 knockdown in neurosphere cells led to increased expression of differentiation markers GFAP and Tuj1. Furthermore, ACSVL3 knockdown reduced anchorage-independent neurosphere cell growth, neurosphere-forming capacity as well as self-renewal of these GBM stem cell enriched neurosphere cultures. In vivo studies revealed that ACSVL3 loss-of-function substantially inhibited the ability of neurosphere cells to propagate orthotopic tumor xenografts. A link between ACSVL3 and cancer stem cell phenotype was further established by the findings that ACSVL3 expression was regulated by receptor tyrosine kinase pathways that support GBM stem cell self-renewal and tumor initiation, including EGFR and HGF/c-Met pathways.

Conclusions

Our findings indicate that the lipid metabolism enzyme ACSVL3 is involved in GBM stem cell maintenance and the tumor-initiating capacity of GBM stem cell enriched-neurospheres in animals.

【 授权许可】

   
2014 Sun et al.; licensee BioMed Central Ltd.

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【 参考文献 】
  • [1]Menendez JA, Lupu R: Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat Rev Cancer 2007, 7(10):763-777.
  • [2]Kuhajda FP: Fatty-acid synthase and human cancer: new perspectives on its role in tumor biology. Nutrition 2000, 16(3):202-208.
  • [3]Swinnen JV, Brusselmans K, Verhoeven G: Increased lipogenesis in cancer cells: new players, novel targets. Curr Opin Clin Nutr Metab Care 2006, 9(4):358-365.
  • [4]Tong L: Acetyl-coenzyme A carboxylase: crucial metabolic enzyme and attractive target for drug discovery. Cell Mol Life Sci: CMLS 2005, 62(16):1784-1803.
  • [5]Lupu R, Menendez JA: Pharmacological inhibitors of Fatty Acid Synthase (FASN)–catalyzed endogenous fatty acid biogenesis: a new family of anti-cancer agents? Curr Pharm Biotechnol 2006, 7(6):483-493.
  • [6]Brusselmans K, De Schrijver E, Verhoeven G, Swinnen JV: RNA interference-mediated silencing of the acetyl-CoA-carboxylase-alpha gene induces growth inhibition and apoptosis of prostate cancer cells. Cancer Res 2005, 65(15):6719-6725.
  • [7]Mashima T, Seimiya H, Tsuruo T: De novo fatty-acid synthesis and related pathways as molecular targets for cancer therapy. Br J Cancer 2009, 100(9):1369-1372.
  • [8]Watkins PA: Fatty acid activation. Prog Lipid Res 1997, 36(1):55-83.
  • [9]Watkins PA: Very-long-chain acyl-CoA synthetases. J Biol Chem 2008, 283(4):1773-1777.
  • [10]Watkins PA, Ellis JM: Peroxisomal acyl-CoA synthetases. Biochim Biophys Acta 2012, 1822(9):1411-1420.
  • [11]Cao Y, Dave KB, Doan TP, Prescott SM: Fatty acid CoA ligase 4 is up-regulated in colon adenocarcinoma. Cancer Res 2001, 61(23):8429-8434.
  • [12]Monaco ME, Creighton CJ, Lee P, Zou X, Topham MK, Stafforini DM: Expression of long-chain fatty acyl-CoA synthetase 4 in breast and prostate cancers is associated with sex steroid hormone receptor negativity. Transl Oncol 2010, 3(2):91-98.
  • [13]Sung YK, Park MK, Hong SH, Hwang SY, Kwack MH, Kim JC, Kim MK: Regulation of cell growth by fatty acid-CoA ligase 4 in human hepatocellular carcinoma cells. Exp Mol Med 2007, 39(4):477-482.
  • [14]Pei Z, Sun P, Huang P, Lal B, Laterra J, Watkins PA: Acyl-CoA synthetase VL3 knockdown inhibits human glioma cell proliferation and tumorigenicity. Cancer Res 2009, 69(24):9175-9182.
  • [15]Yamashita Y, Kumabe T, Cho YY, Watanabe M, Kawagishi J, Yoshimoto T, Fujino T, Kang MJ, Yamamoto TT: Fatty acid induced glioma cell growth is mediated by the acyl-CoA synthetase 5 gene located on chromosome 10q25.1-q25.2, a region frequently deleted in malignant gliomas. Oncogene 2000, 19(51):5919-5925.
  • [16]Galli R, Binda E, Orfanelli U, Cipelletti B, Gritti A, De Vitis S, Fiocco R, Foroni C, Dimeco F, Vescovi A: Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res 2004, 64(19):7011-7021.
  • [17]Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD, Dirks PB: Identification of human brain tumour initiating cells. Nature 2004, 432(7015):396-401.
  • [18]Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, Dewhirst MW, Bigner DD, Rich JN: Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 2006, 444(7120):756-760.
  • [19]Dirks PB: Brain tumor stem cells: the cancer stem cell hypothesis writ large. Mol Oncol 2010, 4(5):420-430.
  • [20]Pei Z, Fraisl P, Berger J, Jia Z, Forss-Petter S, Watkins PA: Mouse very long-chain Acyl-CoA synthetase 3/fatty acid transport protein 3 catalyzes fatty acid activation but not fatty acid transport in MA-10 cells. J Biol Chem 2004, 279(52):54454-54462.
  • [21]Ying M, Wang S, Sang Y, Sun P, Lal B, Goodwin CR, Guerrero-Cazares H, Quinones-Hinojosa A, Laterra J, Xia S: Regulation of glioblastoma stem cells by retinoic acid: role for Notch pathway inhibition. Oncogene 2011, 30(31):3454-3467.
  • [22]Wang SD, Rath P, Lal B, Richard JP, Li Y, Goodwin CR, Laterra J, Xia S: EphB2 receptor controls proliferation/migration dichotomy of glioblastoma by interacting with focal adhesion kinase. Oncogene 2012, 31(50):5132-5243.
  • [23]Chaichana K, Zamora-Berridi G, Camara-Quintana J, Quinones-Hinojosa A: Neurosphere assays: growth factors and hormone differences in tumor and nontumor studies. Stem Cells 2006, 24(12):2851-2857.
  • [24]Bar EE, Chaudhry A, Lin A, Fan X, Schreck K, Matsui W, Piccirillo S, Vescovi AL, DiMeco F, Olivi A, Eberhart CG: Cyclopamine-mediated hedgehog pathway inhibition depletes stem-like cancer cells in glioblastoma. Stem Cells 2007, 25(10):2524-2533.
  • [25]Sun P, Xia S, Lal B, Eberhart CG, Quinones-Hinojosa A, Maciaczyk J, Matsui W, Dimeco F, Piccirillo SM, Vescovi AL, Laterra J: DNER, an epigenetically modulated gene, regulates glioblastoma-derived neurosphere cell differentiation and tumor propagation. Stem Cells 2009, 27(7):1473-1486.
  • [26]Li Y, Li A, Glas M, Lal B, Ying M, Sang Y, Xia S, Trageser D, Guerrero-Cazares H, Eberhart CG, Quinones-Hinojosa A, Scheffler B, Laterra J: c-Met signaling induces a reprogramming network and supports the glioblastoma stem-like phenotype. Proc Natl Acad Sci U S A 2011, 108(24):9951-9956.
  • [27]Reznik TE, Sang Y, Ma Y, Abounader R, Rosen EM, Xia S, Laterra J: Transcription-dependent epidermal growth factor receptor activation by hepatocyte growth factor. Mol Cancer Res 2008, 6(1):139-150.
  • [28]Lal B, Xia S, Abounader R, Laterra J: Targeting the c-Met pathway potentiates glioblastoma responses to gamma-radiation. Clin Cancer Res 2005, 11(12):4479-4486.
  • [29]Wang SD, Bar EE, Chaudhry A, Lin A, Fan X, Schreck K, Matsui W, Piccirillo S, Vescovi AL, DiMeco F, Olivi A, Eberhart CG: EphB2 receptor controls proliferation/migration dichotomy of glioblastoma by interacting with focal adhesion kinase. Oncogene 2012, 31(50):5132-5143.
  • [30]Ying M, Sang Y, Li Y, Guerrero-Cazares H, Quinones-Hinojosa A, Vescovi AL, Eberhart CG, Xia S, Laterra J: Kruppel-like family of transcription factor 9, a differentiation-associated transcription factor, suppresses Notch1 signaling and inhibits glioblastoma-initiating stem cells. Stem Cells 2011, 29(1):20-31.
  • [31]Kuhajda FP, Jenner K, Wood FD, Hennigar RA, Jacobs LB, Dick JD, Pasternack GR: Fatty acid synthesis: a potential selective target for antineoplastic therapy. Proc Natl Acad Sci U S A 1994, 91(14):6379-6383.
  • [32]Orita H, Coulter J, Lemmon C, Tully E, Vadlamudi A, Medghalchi SM, Kuhajda FP, Gabrielson E: Selective inhibition of fatty acid synthase for lung cancer treatment. Clin Cancer Res 2007, 13(23):7139-7145.
  • [33]Vazquez-Martin A, Colomer R, Brunet J, Menendez JA: Pharmacological blockade of fatty acid synthase (FASN) reverses acquired autoresistance to trastuzumab (Herceptin by transcriptionally inhibiting ‘HER2 super-expression’ occurring in high-dose trastuzumab-conditioned SKBR3/Tzb100 breast cancer cells. Int J Oncol 2007, 31(4):769-776.
  • [34]Watkins PA, Maiguel D, Jia Z, Pevsner J: Evidence for 26 distinct acyl-coenzyme A synthetase genes in the human genome. J Lipid Res 2007, 48(12):2736-2750.
  • [35]Das UN: Essential fatty acids and their metabolites as modulators of stem cell biology with reference to inflammation, cancer, and metastasis. Cancer Metastasis Rev 2011, 30(3–4):311-324.
  • [36]Herrmann T, van der Hoeven F, Grone HJ, Stewart AF, Langbein L, Kaiser I, Liebisch G, Gosch I, Buchkremer F, Drobnik W, Schmitz G, Stremmel W: Mice with targeted disruption of the fatty acid transport protein 4 (Fatp 4, Slc27a4) gene show features of lethal restrictive dermopathy. J Cell Biol 2003, 161(6):1105-1115.
  • [37]Das UN, Begin ME, Ells G: Fatty acid changes during the induction of differentiation of human promyelocytic leukemia (HL-60) cells by phorbolmyristate acetate. Prostaglandins Leukot Essent Fatty Acids 1992, 46(3):235-239.
  • [38]Finstad HS, Kolset SO, Holme JA, Wiger R, Farrants AK, Blomhoff R, Drevon CA: Effect of n-3 and n-6 fatty acids on proliferation and differentiation of promyelocytic leukemic HL-60 cells. Blood 1994, 84(11):3799-3809.
  • [39]Kawakita E, Hashimoto M, Shido O: Docosahexaenoic acid promotes neurogenesis in vitro and in vivo. Neuroscience 2006, 139(3):991-997.
  • [40]Varney ME, Hardman WE, Sollars VE: Omega 3 fatty acids reduce myeloid progenitor cell frequency in the bone marrow of mice and promote progenitor cell differentiation. Lipids Health Dis 2009, 8:9. BioMed Central Full Text
  • [41]Hall AM, Wiczer BM, Herrmann T, Stremmel W, Bernlohr DA: Enzymatic properties of purified murine fatty acid transport protein 4 and analysis of acyl-CoA synthetase activities in tissues from FATP4 null mice. J Biol Chem 2005, 280(12):11948-11954.
  • [42]Kim JH, Lewin TM, Coleman RA: Expression and characterization of recombinant rat Acyl-CoA synthetases 1, 4, and 5. Selective inhibition by triacsin C and thiazolidinediones. J Biol Chem 2001, 276(27):24667-24673.
  • [43]Li H, Black PN, Chokshi A, Sandoval-Alvarez A, Vatsyayan R, Sealls W, DiRusso CC: High-throughput screening for fatty acid uptake inhibitors in humanized yeast identifies atypical antipsychotic drugs that cause dyslipidemias. J Lipid Res 2008, 49(1):230-244.
  • [44]Van Horn CG, Caviglia JM, Li LO, Wang S, Granger DA, Coleman RA: Characterization of recombinant long-chain rat acyl-CoA synthetase isoforms 3 and 6: identification of a novel variant of isoform 6. Biochemistry 2005, 44(5):1635-1642.
  • [45]Stahl A, Gimeno RE, Tartaglia LA, Lodish HF: Fatty acid transport proteins: a current view of a growing family. Trends Endocrinol Metab 2001, 12(6):266-273.
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