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Biochim Biophys Acta. 2013 Dec;1831(12):1657-64. doi: 10.1016/j.bbalip.2013.07.016. Epub 2013 Aug 9.

Novel off-target effect of tamoxifen--inhibition of acid ceramidase activity in cancer cells.

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John Wayne Cancer Institute at Saint John's Health Center, Department of Experimental Therapeutics, Santa Monica, CA 90404, USA.


Acid ceramidase (AC), EC, a lysosomal enzyme, catalyzes the hydrolysis of ceramide to constituent sphingoid base, sphingosine, and fatty acid. Because AC regulates the levels of pro-apoptotic ceramide and mitogenic sphingosine-1-phosphate, it is considered an apt target in cancer therapy. The present study reveals, for the first time, that the prominent antiestrogen, tamoxifen, is a pan-effective AC inhibitor in the low, single digit micromolar range, as demonstrated in a wide spectrum of cancer cell types, prostate, pancreatic, colorectal, and breast. Prostate cancer cells were chosen for the detailed investigations. Treatment of intact PC-3 cells with tamoxifen produced time- and dose-dependent inhibition of AC activity. Tamoxifen did not impact cell viability nor did it inhibit AC activity in cell-free assays. In pursuit of mechanism of action, we demonstrate that tamoxifen induced time-, as early as 5min, and dose-dependent, as low as 5μM, increases in lysosomal membrane permeability (LMP), and time- and dose-dependent downregulation of AC protein expression. Assessing various protease inhibitors revealed that a cathepsin B inhibitor blocked tamoxifen-elicited downregulation of AC protein; however, this action failed to restore AC activity unless assayed in a cell-free system at pH4.5. In addition, pretreatment with tamoxifen inhibited PC-3 cell migration. Toremifene, an antiestrogen structurally similar to tamoxifen, was also a potent inhibitor of AC activity. This study reveals a new, off-target action of tamoxifen that may be of benefit to enhance anticancer therapies that either incorporate ceramide or target ceramide metabolism.


AC; AO; Acid ceramidase; Antiestrogen; Ceramide; GC; LMP; Lysosomal protease; N-oleoylethanolamine; NOE; PBS; PBST; PMSF; S1-P; SK; Tamoxifen; acid ceramidase; acridine orange; glucosylceramide; lysosomal membrane permeability; phenylmethylsulfonyl fluoride; phosphate-buffered saline; phosphate-buffered saline with Tween-20; sphingosine 1-phosphate; sphingosine kinase

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