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

access via your institution ACCESS OPTIONS Access through your institution Subscribe to this journal Receive 4 print issues and online access $259.00 per year only $64.75 per issue Learn

more Buy this article * Purchase on SpringerLink * Instant access to full article PDF Buy now Prices may be subject to local taxes which are calculated during checkout ADDITIONAL ACCESS

OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS INHIBITION OF CAMKK2 IMPAIRS AUTOPHAGY AND

CASTRATION-RESISTANT PROSTATE CANCER VIA SUPPRESSION OF AMPK-ULK1 SIGNALING Article 02 February 2021 TARGETING DGAT1 INHIBITS PROSTATE CANCER CELLS GROWTH BY INDUCING AUTOPHAGY FLUX BLOCKAGE

VIA OXIDATIVE STRESS Article 16 November 2023 TARGETING SPHK1/2 BY SKI-178 INHIBITS PROSTATE CANCER CELL GROWTH Article Open access 21 August 2023 REFERENCES * Jemal A, Siegel R, Xu J, Ward

E . Cancer Statistics, 2010. _CA Cancer J Clin_ 2010; 60: 277–300. Article  PubMed  Google Scholar  * 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  * Ogretmen B, Hannun YA . Biologically active sphingolipids in cancer pathogenesis and treatment. _Nat Rev

Cancer_ 2004; 4: 604–616. Article  CAS  PubMed  Google Scholar  * 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  * 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  * 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  * 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  * 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  * Klionsky DJ, Emr SD . Autophagy as a regulated pathway of

cellular degradation. _Science_ 2000; 290: 1717–1721. Article  CAS  PubMed  PubMed Central  Google Scholar  * Levine B, Kroemer G . Autophagy in the pathogenesis of disease. _Cell_ 2008;

132: 27–42. Article  CAS  PubMed  PubMed Central  Google Scholar  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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

  * 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  * 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  Download references 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. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Biology, Francis Marion University, Florence, SC, USA

L S Turner * Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA J C Cheng, T H Beckham, J S Norris & X Liu * Department of Urology,

Medical University of South Carolina, Charleston, SC, USA T E Keane Authors * L S Turner View author publications You can also search for this author inPubMed Google Scholar * J C Cheng View

author publications You can also search for this author inPubMed Google Scholar * T H Beckham View author publications You can also search for this author inPubMed Google Scholar * T E

Keane View author publications You can also search for this author inPubMed Google Scholar * J S Norris View author publications You can also search for this author inPubMed Google Scholar *

X Liu View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to L S Turner. ETHICS DECLARATIONS COMPETING INTERESTS The

authors declare no conflict of interest. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE 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 Download citation * Received: 14 June 2010 * Revised: 27 September 2010 * Accepted: 29 September 2010 * Published: 30 November 2010 * Issue Date: March

2011 * DOI: https://doi.org/10.1038/pcan.2010.47 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a shareable link is

not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * autophagy * acid ceramidase * sphingolipids *

ceramide * apoptosis