The Effect of Silencing the Genes Responsible for the Level of Sphingosine-1-phosphate on the Apoptosis of Colon Cancer Cells

Abstract

Sphingosine-1-phosphate (S1P) and ceramides (Cer) are engaged in key events of signal transduction, but their involvement in the pathogenesis of colorectal cancer is not conclusive. The aim of our study was to investigate how the modulation of sphingolipid metabolism through the silencing of the genes involved in the formation (SPHK1) and degradation (SGPL1) of sphingosine-1-phosphate would affect the sphingolipid profile and apoptosis of HCT-116 human colorectal cancer cells. Silencing of SPHK1 expression decreased S1P content in HCT-116 cells, which was accompanied by an elevation in sphingosine, C18:0-Cer, and C18:1-Cer, increase in the expression and activation of Caspase-3 and -9, and augmentation of apoptosis. Interestingly, silencing of SGLP1 expression increased cellular content of both the S1P and Cer (C16:0-; C18:0-; C18:1-; C20:0-; and C22:0-Cer), yet inhibited activation of Caspase-3 and upregulated protein expression of Cathepsin-D. The above findings suggest that modulation of the S1P level and S1P/Cer ratio regulates both cellular apoptosis and CRC metastasis through Cathepsin-D modulation. The cellular ratio of S1P/Cer seems to be a crucial component of the above mechanism.

Diverse Sphingolipid Profiles in Rectal and Colon Cancer

“…Sphingosine-1-phosphate (S1P) is pro-proliferative agent, while Cer and sphingosine (Sph) are generally pro-apoptotic compounds [ 3 ]. Recent findings suggest that modulation of the S1P/Cer ratio regulates both cellular apoptosis and CRC metastasis through Cathepsin-D modulation [ 10 ]. On the other hand, long-chain and very-long-chain Cer may have the opposite effect on CRC and a disequilibrium between Cer with various fatty acyl chain lengths could be crucial for cancer progression [ 11 ].…”