Journal
EXPERIMENTAL CELL RESEARCH
Volume 314, Issue 8, Pages 1860-1868Publisher
ELSEVIER INC
DOI: 10.1016/j.yexcr.2008.02.008
Keywords
apoptosis; ceramide; dihydroceramide; electrospray ionization/double mass; spectrometry; PDT; phthalocyanine Pc 4; sphingomyelin synthase
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Funding
- NCI NIH HHS [R01 CA077475, R01 CA77475, R01 CA077475-08] Funding Source: Medline
- NCRR NIH HHS [C06 RR018823] Funding Source: Medline
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We have shown that overexpression of SMS1, an enzyme that converts de novo ceramide into sphingomyelin, is accompanied by attenuated ceramide response and apoptotic resistance after photodamage with the photosensitizer Pc 4 (photodynamic therapy; PDT). To test whether SMS1 overexpression-related effects after PDT can be reversed, in this study SMS1 was downregulated in Jurkat T lymphoma/leukemia cells using small inhibitory RNA (siRNA) for SMS1. Compared to scrambled (control) siRNA-transfectants, in SMS1 siRNA-transfected cells the activity of SMS at rest was downregulated with concomitant decrease in sphingomyelin mass. In SMS1 siRNA-transfected cells increases in ceramides were higher than in control siRNA-transfectants after PDT. Similar findings were obtained for dihydroceramides suggesting the involvement of de novo ceramide pathway. PDT-induced DEVDase (caspase-3-like) activation was enhanced in SMS1 siRNA-transfected cells compared to their control counterparts. The data show that RNA interference-dependent downregulation of SMS1 is associated with increased accumulation of ceramide and dihydroceramide with concomitant sensitization of cells to apoptosis after photodamage. Similarly, in SMS2 siRNA-transfected cells, downregulation of SMS activity was accompanied by potentiated DEVDase activation post-photodamage. These findings suggest that SMS is a potential novel molecular target that can augment therapeutic efficacy of PDT. (C) 2008 Elsevier Inc. All rights reserved.
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