The functional effects of acid ceramidase over-expression in prostate cancer progression and resistance to chemotherapy

Authors:
  • WMWilliam D. Meacham
    William D. Meacham
  • ABAiping Bai
    Aiping Bai
  • VAViviane Anelli
    Viviane Anelli
  • AMAyman E.M. Mahdy
    Ayman E.M. Mahdy
  • LTLorianne S. Turner
    Lorianne S. Turner
  • JCJoe Cheng
    Joe Cheng
  • ABAlicja Bielawska
    Alicja Bielawska
  • JBJacek Bielawski
    Jacek Bielawski
  • TKThomas E. Keane
    Thomas E. Keane
  • YHYusuf A. Hannun
    Yusuf A. Hannun
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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 over-expression (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...