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Basic Research

Autophagy is increased in prostate cancer cells overexpressing acid ceramidase and enhances resistance to C6 ceramide

Prostate Cancer and Prostatic Diseases volume 14, pages 30–37 (2011)Cite this article

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Abstract

Acid ceramidase (AC) overexpression has been observed in prostate cancer cell lines and primary tumors, and contributes to resistance to chemotherapy and radiation. The consequence of AC overexpression is the ability to convert ceramide, which is often produced as a proapoptotic response to stress, to sphingosine, which can then be converted to the prosurvival molecule sphingosine-1-phosphate. In addition to their ability to metabolize ceramide produced in response to stress, we show here that prostate cancer cell lines overexpressing AC also have increased lysosomal density and increased levels of autophagy. Furthermore, pretreatment with 3-methyladenine restores sensitivity of these cells to treatment with C6 ceramide. We also observed increased expression of the lysosomal stabilizing protein KIF5B and increased sensitivity to the lysosomotropic agent LCL385. Thus, we conclude that AC overexpression increases autophagy in prostate cancer cells, and that increased autophagy enhances resistance to ceramide.

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References

  1. Jemal A, Siegel R, Xu J, Ward E . Cancer Statistics, 2010. CA Cancer J Clin 2010; 60: 277–300.

    Article  PubMed  Google Scholar 

  2. Ries L, Melbert D, Krapcho M, Stinchcomb D, Howlader N, Horner M et al. SEER Cancer Statistics Review, 1975-2005. In: Ries LAG MD, Krapcho M, Stinchcomb DG, Howlader N, Horner MJ, Mariotto A, Miller BA, Feuer EJ, Altekruse SF, Lewis DR, Clegg L, Eisner MP, Reichman M, Edwards BK (ed). National Cancer Institute: Bethesda MD, 2008.

    Google Scholar 

  3. Ogretmen B, Hannun YA . Biologically active sphingolipids in cancer pathogenesis and treatment. Nat Rev Cancer 2004; 4: 604–616.

    Article  CAS  PubMed  Google Scholar 

  4. Norris JS, Bielawska A, Day T, El-Zawahri A, ElOjeimy S, Hannun Y et al. Combined therapeutic use of AdGFPFasL and small molecule inhibitors of ceramide metabolism in prostate and head and neck cancers: a status report. Cancer Gene Ther 2006; 13: 1045–1051.

    Article  CAS  PubMed  Google Scholar 

  5. Seelan RS, Qian C, Yokomizo A, Bostwick DG, Smith DI, Liu W . Human acid ceramidase is overexpressed but not mutated in prostate cancer. Genes Chromosomes Cancer 2000; 29: 137–146.

    Article  CAS  PubMed  Google Scholar 

  6. Saad AF, Meacham WD, Bai A, Anelli V, Elojeimy S, Mahdy AE et al. The functional effects of acid ceramidase overexpression in prostate cancer progression and resistance to chemotherapy. Cancer Biol Ther 2007; 6: 1455–1460.

    Article  CAS  PubMed  Google Scholar 

  7. Mahdy AEM, Cheng JC, Li J, Elojeimy S, Meacham WD, Turner LS et al. Acid ceramidase upregulation in prostate cancer cells confers resistance to radiation: ac inhibition, a potential radiosensitizer. Mol Ther 2009; 17: 430–438.

    Article  CAS  PubMed  Google Scholar 

  8. Morales A, Paris R, Villanueva A, Llacuna L, Garcia-Ruiz C, Fernandez-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.

    Article  CAS  PubMed  Google Scholar 

  9. Klionsky DJ, Emr SD . Autophagy as a regulated pathway of cellular degradation. Science 2000; 290: 1717–1721.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Levine B, Kroemer G . Autophagy in the pathogenesis of disease. Cell 2008; 132: 27–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kondo Y, Kanzawa T, Sawaya R, Kondo S . The role of autophagy in cancer development and response to therapy. Nat Rev Cancer 2005; 5: 726–734.

    Article  CAS  PubMed  Google Scholar 

  12. Klionsky DJ . Autophagy: from phenomenology to molecular understanding in less than a decade. Nat Rev Mol Cell Biol 2007; 8: 931–937.

    Article  CAS  PubMed  Google Scholar 

  13. Sato K, Tsuchihara K, Fujii S, Sugiyama M, Goya T, Atomi Y et al. Autophagy is activated in colorectal cancer cells and contributes to the tolerance to nutrient deprivation. Cancer Res 2007; 67: 9677–9684.

    Article  CAS  PubMed  Google Scholar 

  14. Fujii S, Mitsunaga S, Yamazaki M, Hasebe T, Ishii G, Kojima M et al. Autophagy is activated in pancreatic cancer cells and correlates with poor patient outcome. Cancer Sci 2008; 99: 1813–1819.

    Article  CAS  PubMed  Google Scholar 

  15. Kang R, Tang D, Schapiro NE, Livesey KM, Farkas A, Loughran P et al. The receptor for advanced glycation end products (RAGE) sustains autophagy and limits apoptosis, promoting pancreatic tumor cell survival. Cell Death Differ 2009; 17: 666–676.

    Article  PubMed  Google Scholar 

  16. Vazquez-Martin A, Oliveras-Ferraros C, Menendez JA . Autophagy facilitates the development of breast cancer resistance to the anti-HER2 monoclonal antibody trastuzumab. PLoS One 2009; 4: e6251.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Elojeimy S, Liu X, McKillop JC, El-Zawahry AM, Holman DH, Cheng JY et al. Role of acid ceramidase in resistance to FasL: therapeutic approaches based on acid ceramidase inhibitors and FasL gene therapy. Mol Ther 2007; 15: 1259–1263.

    Article  CAS  PubMed  Google Scholar 

  18. Holman DH, Turner LS, El-Zawahry A, Elojeimy S, Liu X, Bielawski J et al. Lysosomotropic acid ceramidase inhibitor induces apoptosis in prostate cancer cells. Cancer Chemother Pharmacol 2008; 61: 231–242.

    Article  CAS  PubMed  Google Scholar 

  19. Liu X, Elojeimy S, Turner LS, Mahdy AE, Zeidan YH, Bielawska A et al. Acid ceramidase inhibition: a novel target for cancer therapy. Front Biosci 2008; 13: 2293–2298.

    Article  CAS  PubMed  Google Scholar 

  20. Brothman AR, Lesho LJ, Somers KD, Wright GL, Merchant Jr DJ . Phenotypic and cytogenetic characterization of a cell line derived from primary prostatic carcinoma. Int J Cancer 1989; 44: 898–903.

    Article  CAS  PubMed  Google Scholar 

  21. Cardoso CM, Groth-Pedersen L, Hoyer-Hansen M, Kirkegaard T, Corcelle E, Andersen JS et al. Depletion of kinesin 5B affects lysosomal distribution and stability and induces peri-nuclear accumulation of autophagosomes in cancer cells. PLoS One 2009; 4: e4424.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Fehrenbacher N, Bastholm L, Kirkegaard-Sorensen T, Rafn B, Bottzauw T, Nielsen C et al. Sensitization to the lysosomal cell death pathway by oncogene-induced down-regulation of lysosome-associated membrane proteins 1 and 2. Cancer Res 2008; 68: 6623–6633.

    Article  CAS  PubMed  Google Scholar 

  23. Szulc ZM, Mayroo N, Bai A, Bielawski J, Liu X, Norris JS et al. Novel analogs of D-e-MAPP and B13. Part 1: synthesis and evaluation as potential anticancer agents. Bioorg Med Chem 2008; 16: 1015–1031.

    Article  CAS  PubMed  Google Scholar 

  24. Paglin S, Hollister T, Delohery T, Hackett N, McMahill M, Sphicas E et al. A novel response of cancer cells to radiation involves autophagy and formation of acidic vesicles. Cancer Res 2001; 61: 439–444.

    CAS  PubMed  Google Scholar 

  25. Apel A, Herr I, Schwarz H, Rodemann HP, Mayer A . Blocked autophagy sensitizes resistant carcinoma cells to radiation therapy. Cancer Res 2008; 68: 1485–1494.

    Article  CAS  PubMed  Google Scholar 

  26. Elojeimy S, Holman DH, Liu X, El-Zawahry A, Villani M, Cheng JC et al. New insights on the use of desipramine as an inhibitor for acid ceramidase. FEBS Lett 2006; 580: 4751–4756.

    Article  CAS  PubMed  Google Scholar 

  27. Nakata T, Hirokawa N . Point mutation of adenosine triphosphate-binding motif generated rigor kinesin that selectively blocks anterograde lysosome membrane transport. J Cell Biol 1995; 131: 1039–1053.

    Article  CAS  PubMed  Google Scholar 

  28. Guenther GG, Peralta ER, Rosales KR, Wong SY, Siskind LJ, Edinger AL . Ceramide starves cells to death by downregulating nutrient transporter proteins. Proc Natl Acad Sci USA 2008; 105: 17402–17407.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank the Lipidomics Core Facility Synthetic Subcore (MUSC) for ceramide and LCL385, Youssef Zeidan (Department of Biochemistry and Molecular Biology, MUSC) for the AC-V5 and lacZ-V5 plasmid constructs, Dr Noboru Mizushima (Tokyo Medical and Dental University, Japan) for the LC3 cDNA, Dr Christina Voelkel-Johnson (MUSC) for use of the fluorescent microscope, Rick Peppler (MUSC Hollings Cancer Center Flow Cytometry & Cell Sorting Core Facility) for assistance with flow cytometry, Margaret Kelly (MUSC Hollings Cancer Center Cell and Molecular Core Facility) for assistance with confocal microscopy, Donald Rao (Gradalis; Dallas, TX, USA) for assistance with siRNA design and Janie Nelson (Department of Microbiology and Immunology, MUSC) for secretarial assistance. This work was supported by NIH/NCI 1 T32 CA119945 and NIH/NCI P01 CA097132.

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Authors and Affiliations

  1. Department of Biology, Francis Marion University, Florence, SC, USA

    L S Turner

  2. Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA

    J C Cheng, T H Beckham, J S Norris & X Liu

  3. Department of Urology, Medical University of South Carolina, Charleston, SC, USA

    T E Keane

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  1. L S Turner
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Correspondence to L S Turner.

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Turner, L., Cheng, J., Beckham, T. et al. Autophagy is increased in prostate cancer cells overexpressing acid ceramidase and enhances resistance to C6 ceramide. Prostate Cancer Prostatic Dis 14, 30–37 (2011). https://doi.org/10.1038/pcan.2010.47

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