The emerging roles of sphingosine 1-phosphate and SphK1 in cancer resistance: a promising therapeutic target

Abstract

Cancer chemoresistance is a problematic dilemma that significantly restrains numerous cancer management protocols. It can promote cancer recurrence, spreading of cancer, and finally, mortality. Accordingly, enhancing the responsiveness of cancer cells towards chemotherapies could be a vital approach to overcoming cancer chemoresistance. Tumour cells express a high level of sphingosine kinase-1 (SphK1), which acts as a protooncogenic factor and is responsible for the synthesis of sphingosine-1 phosphate (S1P). S1P is released through a Human ATP-binding cassette (ABC) transporter to interact with other phosphosphingolipids components in the interstitial fluid in the tumor microenvironment (TME), provoking communication, progression, invasion, and tumor metastasis. Also, S1P is associated with several impacts, including anti-apoptotic behavior, metastasis, mesenchymal transition (EMT), angiogenesis, and chemotherapy resistance. Recent reports addressed high levels of S1P in several carcinomas, including ovarian, prostate, colorectal, breast, and HCC. Therefore, targeting the S1P/SphK signaling pathway is an emerging therapeutic approach to efficiently attenuate chemoresistance. In this review, we comprehensively discussed S1P functions, metabolism, transport, and signaling. Also, through a bioinformatic framework, we pointed out the alterations of SphK1 gene expression within different cancers with their impact on patient survival, and we demonstrated the protein-protein network of SphK1, elaborating its sparse roles. Furthermore, we made emphasis on different machineries of cancer resistance and the tight link with S1P. We evaluated all publicly available SphK1 inhibitors and their inhibition activity using molecular docking and how SphK1 inhibitors reduce the production of S1P and might reduce chemoresistance, an approach that might be vital in the course of cancer treatment and prognosis.

Keywords: Cancer; Chemoresistance; Recurrence; S1P; SphK1; TME.

Fig. 1

The bioinformatic framework analysis of SphK1. A The crystal structure of SphK1. B SphK1 subcellular localization in the cell, more abundance is relative to a darker color. C Protein–protein interactions of the SphK1 protein by STRING database. [Data source: UniProt database, The Human Protein Atlas, STRING version 11.0]

Fig. 2

Kaplan–Meier survival plot using KM-plotter for SphK1 gene expression across different carcinomas, the upper partition (A) represents worse prognosis associated with low expression of the enzyme, while the lower partition (B) represents worse prognosis with high expression of the enzyme. Red-labeled cancers imply statistical significance in this type of cancer. [Data source: Kaplan‐Meier plotter database]

Fig. 3

Overview of S1P metabolism. The de novo pathway begins with small molecules such as serine and palmitoyl-CoA and subsequently by the activity of SPT, KDHR, CerS, and dihydro-ceramide desaturase forming ceramide which can be utilized for S1P formation. The acidic environment of endosomes and lysosomes degradation of complex sphingolipids, including sphingomyelin, forms sphingosine, then are phosphorylated by SphK1 and SphK2. Furthermore, plasma membrane sphingomyelin by the action of sphingomyelinase to ceramide. SPT: Serine palmitoyl transferase; KDHR: 3-ketodihydrosphingosine reductase; CerS: ceramides synthases; SphK1/2: Sphingosine kinase 1/2; SGPP1/2: S1P phosphatase. The chemical structures used in the present illustration were drawn using ChemDraw Professional 21.0 software, and the figure was drawn by using Biorender https://www.biorender.com/

Fig. 4

Effect of S1P on cancer cell proliferation. The figure was drawn by using biorender https://www.biorender.com/

Fig. 5

S1P involvement in drug resistance. The figure was drawn by using biorender https://www.biorender.com/

Fig. 6

Generation of Compound 51 after modification of N-(5-alkyloxadiazol-3-yl) benzyl)-3-hydroxypyrrolidine-2-carboxamide scaffold (compound 4). The chemical structures used in the present illustration were drawn using ChemDraw Professional 21.0 software

Fig. 7

Combining fragments of two hits of molecules (12 and 20a) to generate PF543. The chemical structures used in the present illustration were drawn using ChemDraw Professional 21.0 software

Fig. 8

SphK2 phosphorylation promotes apoptosis via SG-12 and its inhibitory effect. The figure was drawn by using biorender https://www.biorender.com/

Fig. 9

a, b 3D and 2D molecular docking results, respectively, for the co-crystallized of (2S,3R,4E)-2-aminooctadec-4-ene-1,3-diol (SQS) in SphK1. a Alkyl and pi-alkyl were removed, and the surface was optimized to atom charge. b 2D interaction diagram showing SQS docking pose interactions with the enzyme, including two amino acids ASP 178 and LEU 268 through attractive charge and conventional hydrogen bond, respectively. The figure was drawn by using MOE.2015 and Discovery Studio Visualizer

Fig. 10

a, b 3D and 2D molecular docking results, respectively, for the reference molecule (PF-543) in SphK1. a Alkyl and pi-alkyl were removed, and the surface was optimized to atom charge. b 2D interaction diagram showing PF-543 docking pose interactions with the enzyme, including GLY26, and SER112 via conventional hydrogen bond. The figure was drawn by using MOE.2015 and Discovery Studio Visualizer

Fig. 11

a, b 3D and 2D molecular docking results, respectively, for the inhibitor SG14 in SphK1. a Alkyl and pi-alkyl were removed, and the surface was optimized to atom charge. b 2D interaction diagram showing SG14 docking pose interactions with the enzyme, including GLY113 and ARG191, via conventional hydrogen bond. The figure was drawn by using MOE.2015 and Discovery Studio Visualizer