Open AccessSphingosine kinase‐1 inhibition sensitizes curcumin‐induced growth inhibition and apoptosis in ovarian cancer cells
Author(s) -
Yang Yanli,
Ji Chao,
Cheng Lei,
He Li,
Lu Chuncheng,
Wang Rong,
Bi Zhigang
Publication year - 2012
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2012.02335.x
Subject(s) - curcumin , ceramide , sphingosine kinase 1 , ovarian cancer , apoptosis , sphingosine , cancer cell , cancer research , small interfering rna , growth inhibition , chemistry , kinase , pharmacology , biology , cancer , medicine , cell culture , sphingosine 1 phosphate , transfection , biochemistry , receptor , genetics
Recent published studies suggest that increasing levels of ceramides enhance the chemo‐sensitivity of curcumin. Using in vitro approaches, we analyzed the impact of sphingosine kinase‐1 ( S ph K ‐1) inhibition on ceramide production, and evaluated SphK1 inhibitor II ( SKI ‐ II ) as a potential curcumin chemo‐sensitizer in ovarian cancer cells. We found that S ph K 1 is overexpressed in ovarian cancer patients' tumor tissues and in cultured ovarian cancer cell lines. Inhibition of S ph K 1 by SKI ‐ II or by RNA interference ( RNA i) knockdown dramatically enhanced curcumin‐induced apoptosis and growth inhibition in ovarian cancer cells. SKI ‐ II facilitated curcumin‐induced ceramide production, p38 activation and A kt inhibition. Inhibition of p38 by the pharmacological inhibitor ( SB 203580), a dominant‐negative expression vector, or by RNA i diminished curcumin and SKI ‐ II co‐administration‐induced ovarian cancer cell apoptosis. In addition, restoring A kt activation introducing a constitutively active A kt, or inhibiting ceramide production by fumonisin B 1 also inhibited the curcumin plus SKI ‐ II co‐administration‐induced in vitro anti‐ovarian cancer effect, suggesting that ceramide accumulation, p38 activation and A kt inhibition are downstream effectors. Our findings suggest that low, well‐tolerated doses of SKI ‐ II may offer significant improvement to the clinical curcumin treatment of ovarian cancer. ( Cancer Sci , doi: 10.1111/j.1349‐7006.2012.02335.x, 2012)