The functional effects of acid ceramidase overexpression in prostate cancer progression and resistance to chemotherapy.
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.
Saad
Antonio F
AF
Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
Meacham
William D
WD
Bai
Aiping
A
Anelli
Viviane
V
Elojeimy
Saeed
S
Mahdy
Ayman E M
AE
Turner
Lorianne S
LS
Cheng
Joe
J
Bielawska
Alicja
A
Bielawski
Jacek
J
Keane
Thomas E
TE
Obeid
Lina M
LM
Hannun
Yusuf A
YA
Norris
James S
JS
Liu
Xiang
X
D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D002518:Ceramides / Q000378:metabolism; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D002517:Galactosylgalactosylglucosylceramidase / Q000096:biosynthesis*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology*
D002518:Ceramides; C101954:N-caproylsphingosine; D002517:Galactosylgalactosylglucosylceramidase