Metastasis is the most common cause of death in
colorectal cancer patients.
Fatty acid synthase (FASN) and
sphingosine kinase-1 and -2 (SPHK1 and 2) are overexpressed in many
cancers, including
colorectal cancer. However, the contribution of FASN-mediated upregulation of
sphingolipid metabolism to
colorectal cancer metastasis and the potential of these pathways as targets for therapeutic intervention remain unknown. This study determined that
sphingosine kinases (SPHK) are overexpressed in
colorectal cancer as compared with normal mucosa. FASN expression significantly correlated with SPHK2 expression in data sets from The
Cancer Genome Atlas (TCGA) and a
colorectal cancer tumor microarray. FASN, SPHK1, and SPHK2 colocalized within invadopodia of primary
colorectal cancer cells. Moreover, FASN inhibition decreased SPHK2 expression and the levels of
dihydrosphingosine 1-phosphate (DH-S1P) and
sphingosine 1-phosphate (S1P) in
colorectal cancer cells and
tumor tissues. Inhibition of FASN using
TVB-3664 and
sphingolipid metabolism using
FTY-720 significantly inhibited the ability of primary
colorectal cancer cells to proliferate, migrate, form focal adhesions, and degrade
gelatin. Inhibition of the FASN/SPHK/S1P axis was accompanied by decreased activation of p-MET, p-FAK, and p-PAX. S1P treatment rescued FASN-mediated inhibition of these
proteins, suggesting that FASN promotes metastatic properties of
colorectal cancer cells, in part, through an increased
sphingolipid metabolism. These data demonstrate that upregulation of the FASN/SPHK/S1P axis promotes
colorectal cancer progression by enhancing proliferation, adhesion, and migration. IMPLICATIONS: This study provides a strong rationale for further investigation of the interconnection of de novo lipogenesis and
sphingolipid metabolism that could potentially lead to the identification of new therapeutic targets and strategies for
colorectal cancer.