The functional effects of acid ceramidase overexpression in prostate cancer progression and resistance to chemotherapy

Antonio Saad, William D. Meacham, Aiping Bai, Viviane Anelli, Saeed Elojeimy, Ayman E M Mahdy, Lorianne S. Turner, Joe Cheng, Alicja Bielawska, Jacek Bielawski, Thomas E. Keane, Lina M. Obeid, Yusuf A. Hannun, James S. Norris, Xiang Liu

Research output: Contribution to journalArticle

90 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1455-1460
Number of pages6
JournalCancer Biology and Therapy
Volume6
Issue number9
StatePublished - Sep 1 2007
Externally publishedYes

Keywords

  • Acid ceramidase
  • Drug resistance
  • Migration
  • Prostate cancer
  • Sphingolipids

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

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  • Cite this

    Saad, A., Meacham, W. D., Bai, A., Anelli, V., Elojeimy, S., Mahdy, A. E. M., Turner, L. S., Cheng, J., Bielawska, A., Bielawski, J., Keane, T. E., Obeid, L. M., Hannun, Y. A., Norris, J. S., & Liu, X. (2007). The functional effects of acid ceramidase overexpression in prostate cancer progression and resistance to chemotherapy. Cancer Biology and Therapy, 6(9), 1455-1460.