ROLE OF SPHINGOSINE KINASE 1 IN COLORECTAL CANCER

Abstract

Sphingolipids are major components of the membrane bilayer and they play critical roles in regulating cancer development. The major bioactive sphingolipids, ceramide and sphingosine-1-phosphate (S1P), regulate very distinct cellular functions. Increased levels of ceramide have been shown to promote apoptosis, while increased levels of S1P promote cell proliferation and survival. A `sphingolipid rheostat¿ has been proposed, whereby the relative levels of ceramide to S1P in living cells influence cell fate. The enzyme that is responsible for regulating this sphingolipid rheostat is sphingosine kinase (SphK), which catalyses the phosphorylation of sphingosine to S1P. SphK1 is the primary isoform that reduces pro-apoptotic ceramide levels by shifting the sphingolipid metabolism pathway towards the production of S1P, thereby tilting the rheostat towards cell survival. SphK1 itself acts as an oncogene and is up-regulated in various forms of cancer. SphK1 potentiates cancer progression by sustaining important survival signaling pathways in cancer cells. Its expression correlates with poor prognosis in cancer patients. Therefore, SphK1 is a potential chemotherapy target, in view of the evidence supporting its oncogenic roles. Colorectal cancer is the third most common cancer in the world and the fourth most common cause of death from cancer. It is an aggressive form of cancer for which we lack adequate therapy. Although SphK1 has gained increasing prominence as an oncogenic determinant in several cancers, its potential as a therapeutic target in colorectal cancer remains uncertain. In this project, we provided strong evidence for the emerging importance of SphK1 in colorectal cancer and the potential effectiveness of inhibiting SphK1 activity in chemotherapy. We demonstrated a definite correlation between high SphK1 expression and advanced malignancy as well as poor survival in colorectal adenocarcinoma patients. Antagonism of the SphK1 pathway through a novel SphK1-specific inhibitor, Compound 5c, inhibits cell cycle progression, resulting in the apoptosis of colon cancer cells. SphK1 inhibition sensitizes cancer cells to 5-fluorouracil treatment, suggesting that SphK1 inhibitors should be explored for their potency as adjunct agents in current chemotherapeutic regimes. We further elucidated a novel SphK1-S1P-PKCd-Akt signaling pathway, revealing an alternative mechanism by which SphK1 promotes the survival of colorectal cancer cells through its interactions with PKCd and Akt signaling. Therapeutic strategies that employ the use of SphK1 inhibitors are likely to disrupt these pro-survival mechanisms and drive the colorectal cancer cells towards death. Taken together, SphK1 is an important prognostic and oncogenic determinant in colorectal cancer. Drugs that target SphK1 if developed with acceptable toxicity may present a new therapeutic strategy to treat colorectal cancer.