Sphingosine kinase-1 (SphK1) inhibition sensitizes curcumin-induced growth inhibition and apoptosis in ovarian cancer cells.
Summary of "Sphingosine kinase-1 (SphK1) inhibition sensitizes curcumin-induced growth inhibition and apoptosis in ovarian cancer cells."
Recent studies suggest that increasing level of ceramides enhances the chemo-sensitivity of curcumin. Using in vitro approaches, we here analyzed the impact of sphingosine kinase-1 (SphK-1) inhibition on ceramides production, and evaluated SphK1 inhibitor II (SKI-II) as a potential curcumin chemo-sensitizer in ovarian cancer cells. We found SphK1 is over-expressed in ovarian cancer patients' tumor tissues and in cultured ovarian cancer cell lines. Inhibition of SphK1 by SKI-II or by RNA interference (RNAi) knockdown dramatically enhanced curcumin-induced apoptosis and growth inhibition in ovarian cancer cells. SKI-II facilitated curcumin-induced ceramides production, p38 activation and Akt inhibition. Inhibition of p38 by the pharmacological inhibitor (SB 203580), a dominant-negative expression vector, or by RNAi diminished curcumin and SKI-II co-administration-induced ovarian cancer cell apoptosis, and, to restore Akt activation by introducing a constitutively active Akt (CA-Akt), or to inhibit ceramides production by fumonisin B1 also inhibited curcumin plus SKI-II co-administration-induced in vitro anti-ovarian cancer effect, suggesting that ceramides accumulation, p38 activation and Akt 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 the ovarian cancer.
Affiliation
Department of Otorhinolaryngology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210024, Jiangsu, China.
Journal Details
This article was published in the following journal.
Name: Cancer science
ISSN: 1349-7006
Pages:
Links
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/22594559
- DOI: http://dx.doi.org/10.1111/j.1349-7006.2012.02335.x
Medical and Biotech [MESH] Definitions
Map Kinase Kinase Kinase 2
A 70-kDa MAP kinase kinase kinase with specificity for MAP KINASE KINASE 5. It is activated during the cellular response to GROWTH FACTORS, oxidative stress, and hyperosmotic conditions.
Eif-2 Kinase
A dsRNA-activated cAMP-independent protein serine/threonine kinase that is induced by interferon. In the presence of dsRNA and ATP, the kinase autophosphorylates on several serine and threonine residues. The phosphorylated enzyme catalyzes the phosphorylation of the alpha subunit of EUKARYOTIC INITIATION FACTOR-2, leading to the inhibition of protein synthesis.
Curcumin
A yellow-orange dye obtained from tumeric, the powdered root of CURCUMA longa. It is used in the preparation of curcuma paper and the detection of boron. Curcumin appears to possess a spectrum of pharmacological properties, due primarily to its inhibitory effects on metabolic enzymes.
Map Kinase Kinase Kinase 5
A 150-kDa MAP kinase kinase kinase that may play a role in the induction of APOPTOSIS. It has specificity for MAP KINASE KINASE 3; MAP KINASE KINASE 4; and MAP KINASE KINASE 6.
Receptor, Fibroblast Growth Factor, Type 1
A fibroblast growth factor receptor with specificity for FIBROBLAST GROWTH FACTORS; HEPARAN SULFATE PROTEOGLYCAN; and NEURONAL CELL ADHESION MOLECULES. Several variants of the receptor exist due to multiple ALTERNATIVE SPLICING of its mRNA. Fibroblast growth factor receptor 1 is a tyrosine kinase that transmits signals through the MAP KINASE SIGNALING SYSTEM.
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