Sphingosine 1‐phosphate lyase facilitates cancer progression through converting sphingolipids to glycerophospholipids

Abstract

Background In addition to potent agonist properties for sphingosine 1‐phosphate (S1P) receptors, intracellularly, S1P is an intermediate in metabolic conversion pathway from sphingolipids to glycerolysophospholipids (glyceroLPLs). We hypothesized that this S1P metabolism and its products might possess some novel roles in the pathogenesis of cancer, where S1P lyase (SPL) is a key enzyme. Methods The mRNA levels of sphingolipid‐related and other cancer‐related factors were measured in human hepatocellular carcinoma (HCC), colorectal cancer, and esophageal cancer patients’ tumours and in their adjacent non‐tumour tissues. Phospholipids (PL) and glyceroLPLs were measured by using liquid chromatography‐tandem mass spectrometry (LC‐MS/MS). In‐vitro experiments were performed in Colon 26 cell line with modulation of the SPL and GPR55 expressions. Xenograft model was used for determination of the cancer progression and for pharmacological influence. Results Besides high SPL levels in human HCC and colon cancer, SPL levels were specifically and positively linked with levels of glyceroLPLs, including lysophosphatidylinositol (LPI). Overexpression of SPL in Colon 26 cells resulted in elevated levels of LPI and lysophosphatidylglycerol (LPG), which are agonists of GPR55. SPL overexpression‐enhanced cell proliferation was inhibited by GPR55 silencing. Conversely, inhibition of SPL led to the opposite outcome and reversed by adding LPI, LPG, and metabolites generated during S1P degradation, which is regulated by SPL. The xenograft model results suggested the contribution of SPL and glyceroLPLs to tumour progression depending on levels of SPL and GPR55. Moreover, the pharmacological inhibition of SPL prevented the progression of cancer. The underlying mechanisms for the SPL‐mediated cancer progression are the activation of p38 and mitochondrial function through the LPI, LPG‐GPR55 axis and the suppression of autophagy in a GPR55‐independent manner. Conclusion A new metabolic pathway has been proposed here in HCC and colon cancer, SPL converts S1P to glyceroLPLs, mainly to LPI and LPG, and facilitates cancer development.

Alzheimer’s disease manifests abnormal sphingolipid metabolism

“…In our case, the S1P levels remained unchanged in tissue or cell samples, which is consistent with previous studies ( He et al, 2010 ; Ceccom et al, 2014 ; Couttas et al, 2014 ; Kurano et al, 2022c ), which reported either unchanged or decreased S1P levels and SK activity, suggesting a difficulty to employ S1P receptor agonists. These discrepancies might be attributed to postmortem effects, because S1P can be intracellularly degraded ( Uranbileg et al, 2022 ) or because of the lower accuracy of the comprehensive measuring method in the measurement of S1P versus the specific measuring methods of S1P. In fact, in our previous paper using a specific measuring method of S1P, the brain S1P levels were lower in the AD brains ( Kurano et al, 2022c ).…”

“…Sphingolipids are among the well-studied bioactive lipid mediators, playing crucial roles in the physiology and pathology of human diseases ( Kluk and Hla, 2002 ; Hla, 2003 ; Nakamura et al, 2021 ; Kurano et al, 2022a , b , d ; Uranbileg et al, 2022 ). In the field of neurology, their structural role in cellular membranes, particularly in lipid rafts, is a crucial aspect of their interaction with the amyloid beta (Aβ) metabolism ( Olsen and Faergeman, 2017 ), suggesting the potential to investigate their role in AD.…”

Critical Roles of the Sphingolipid Metabolic Pathway in Liver Regeneration, Hepatocellular Carcinoma Progression and Therapy

“…Fumonisin B1 and SKI II were relatively effective in inhibiting cell proliferation in HepG2 and Huh7.5 cells [ 108 ]. S1P lyase facilitates cancer progression by converting S1P into glycerophospholipids [ 57 ].…”

Identification of pre‐diagnostic lipid sets associated with liver cancer risk using untargeted lipidomics and chemical set analysis: A nested case‐control study within the ATBC cohort

“…52 Negative associations with both ceramides and sphingomyelins suggest that ceramides are probably diverted to the catabolic pathway to generate more pro-growth signaling molecules. Blocking of key enzymes, such as sphingosine kinase 2 (SphK2) 53 and S1P lyase (SPL) 54 in sphingolipids metabolism, 52 has also been shown to block liver cancer growth in cell and animal bioassays. Our results point to a higher activity of ceramidases in liver that can serve to both promote cell survival and to suppress the ceramide dependent apoptotic cascade.…”