The key role of sphingolipid metabolism in cancer: New therapeutic targets, diagnostic and prognostic values, and anti-tumor immunotherapy resistance

Abstract

Biologically active sphingolipids are closely related to the growth, differentiation, aging, and apoptosis of cancer cells. Some sphingolipids, such as ceramides, are favorable metabolites in the sphingolipid metabolic pathway, usually mediating antiproliferative responses, through inhibiting cancer cell growth and migration, as well as inducing autophagy and apoptosis. However, other sphingolipids, such as S1P, play the opposite role, which induces cancer cell transformation, migration and growth and promotes drug resistance. There are also other sphingolipids, as well as enzymes, played potentially critical roles in cancer physiology and therapeutics. This review aimed to explore the important roles of sphingolipid metabolism in cancer. In this article, we summarized the role and value of sphingolipid metabolism in cancer, including the distribution of sphingolipids, the functions, and their relevance to cancer diagnosis and prognosis. We also summarized the known and potential antitumor targets present in sphingolipid metabolism, analyzed the correlation between sphingolipid metabolism and tumor immunity, and summarize the antitumor effects of natural compounds based on sphingolipids. Through the analysis and summary of sphingolipid antitumor therapeutic targets and immune correlation, we aim to provide ideas for the development of new antitumor drugs, exploration of new therapeutic means for tumors, and study of immunotherapy resistance mechanisms.

Identification and validation of a prognostic risk-scoring model based on sphingolipid metabolism-associated cluster in colon adenocarcinoma

“…Sphingolipids play a crucial role in the plasma membrane and have been shown to modulate the activity of surface receptors on immune cell surfaces ( 75 ). These metabolites have a role in the secretion of bioactive mediators such as S1P and ceramides, which control the crucial pathways necessary for the activation of immune cells and affect lymphocyte efflux and migration into the tumour microenvironment (TME) ( 76 ).…”

“…Ceramide promoted the tumor-associated macrophages (TAMs) to differentiate into M1-like macrophages through activation of the protein kinase C pathway ( 77 ). Following this, M1-like macrophages induced tumor death via secreting IL-6, IL-10, IL-12, and TNF-α ( 75 ). Ceramide-mediated alterations of the rate of T helper 1 cell (Th1) and Th2 in host-TME led to TME skewed toward proinflammatory milieu, and then inhibit tumor growth ( 75 ).…”

“…Following this, M1-like macrophages induced tumor death via secreting IL-6, IL-10, IL-12, and TNF-α ( 75 ). Ceramide-mediated alterations of the rate of T helper 1 cell (Th1) and Th2 in host-TME led to TME skewed toward proinflammatory milieu, and then inhibit tumor growth ( 75 ). Moreover, C2-ceramide exerts its anti-tumor activity by increasing the percentage of CD8+T cells and producing perforin and granzyme B ( 77 ).…”

Overexpression of SPHK1 associated with targeted therapy resistance in predicting poor prognosis in renal cell carcinoma

“…A recent study has shown that sphingolipid metabolism plays an important role in sunitinib resistance (6). Sphingosine (Sph) is associated with cell growth arrest and apoptosis and is a ubiquitous component of the cell membrane.…”

Exercise Promotes Pro-Apoptotic Ceramide Signaling in a Mouse Melanoma Model

“…Ceramide is a bioactive lipid molecule that regulates tumor cell proliferation, differentiation, senescence, and apoptosis [ 5 ]. Most often, ceramide promotes apoptosis or inhibits proliferation in tumor cells [ 6 ]. As a central sphingolipid metabolite, pro-apoptotic ceramide can be used to generate pro-survival signaling by sphingosine-1-phosphate (S1P)- or glucosylceramide-converting enzymes.…”