@article{fb43c89f2b6d41448499df077a2fa422,
title = "The functional effects of acid ceramidase overexpression in prostate cancer progression and resistance to chemotherapy",
abstract = "Among the many processes regulating cell death, ceramide signaling is a vital component. We previously determined that acid ceramidase (AC) is upregulated in 60\% of primary prostate cancer (PCa) tissues, suggesting that AC may play a role in tumor development. In order to determine the significance of AC elevation, stable clones of DU145 cells with AC overexpression (AC-EGFP) were generated. Compared to controls (EGFP), AC-EGFP cells exhibited enhanced cell proliferation and migration. Subcutaneous injection of AC-EGFP cells into Nu/Nu mice resulted in larger tumor volumes compared to EGFP controls. Moreover, using the MTS viability assay, AC-EGFP cells were more resistant to cell death induced by doxorubicin, cisplatin, etoposide, gemcitabine or C6-ceramide. Conversely, knock down of AC using siRNA, sensitized AC-EGFP cells to these drugs. In addition, mass spectroscopic analysis of sphingolipids indicated that long chain ceramide levels were decreased in AC-EGFP cells treated with either doxorubicin or etoposide. In conclusion, this study implicates AC as a critical regulator of PCa progression by affecting not only tumor cell proliferation and migration but also responses to drug therapy, suggesting AC as a potential therapeutic target in advanced PCa.",
keywords = "Acid ceramidase, Drug resistance, Migration, Prostate cancer, Sphingolipids",
author = "Saad, \{Antonio F.\} and Meacham, \{William D.\} and Aiping Bai and Viviane Anelli and Saeed Elojeimy and Mahdy, \{Ayman E.M.\} and Turner, \{Lorianne S.\} and Joe Cheng and Alicja Bielawska and Jacek Bielawski and Keane, \{Thomas E.\} and Obeid, \{Lina M.\} and Hannun, \{Yusuf A.\} and Norris, \{James S.\} and Xiang Liu",
note = "Funding Information: Acknowledgements This work was supported by NIH/NCI PO1 CA97132, HCC/ DOD N6311601MD10004, Division of Laboratory Animal Research, NIH, C06 RR015455 and the MUSC Lipidomics Core Facility. The technical assistance of Margaret Kelly of the MUSC Hollings Cancer Center Microscopy Core Facility is highly appreci-ated. Excellent secretarial assistance was provided by Janie Nelson. Figure 6. AC downregulation by siRNA sensitizes AC‑EGFP cells to References doxorubicin‑induced cell toxicity. (A) Western blot showing downregula‑ 1. Greenlee RT, Murray T, Bolden S, Wingo PA. Cancer statistics, 2000. CA: A Cancer Journal tion of AC levels in AC‑EGFP cells following transfection with AC siRNA. for Clinicians 2000; 50:7-33. (B) Sensitization of AC‑EGFP cells to doxorubicin (750 ng/ml) was observed of Cancer 2004; 91:1005-11.2.Canil CM, Tannock IF. Is there a role for chemotherapy in prostate cancer? British Journal following AC siRNA treatment for 48 hrs using the MTS assay (*p = 0.0001 3. Ward JF, Slezak JM, Blute ML, Bergstralh EJ, Zincke H. Radical prostatectomy for clinically AC siRNA {\textcopyright}vs SC‑siRNA).2008 LANDES BIOSCIENCE advanced (cT3) prostate cancer since the advent of prostate-specific antigen testing: 15-year outcome. BJU International 2005; 95:751-6. 4. Dong JT, Lamb PW, Rinker-Schaeffer CW, Vukanovic J, Ichikawa T, Isaacs JT, Barrett JC. KAI1, a metastasis suppressor gene for prostate cancer on human chromosome 11p11.2. Science NY 1995; 268:884-6. 5. Thompson TC. Growth factors and oncogenes in prostate cancer. Cancer Cells 1990; 2:345-54. 6. Umbas R, Isaacs WB, Bringuier PP, Schaafsma HE, Karthaus HF, Oosterhof GO, Debruyne FM, Schalken JA. Decreased E-cadherin expression is associated with poor prognosis in patients with prostate cancer. Cancer Res 1994; 54:3929-33.",
year = "2007",
month = sep,
doi = "10.4161/cbt.6.9.4623",
language = "English (US)",
volume = "6",
pages = "1455--1460",
journal = "Cancer Biology and Therapy",
issn = "1538-4047",
publisher = "Taylor and Francis Ltd.",
number = "9",
}