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Open Access 01-12-2024 | Review

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

Authors: Samar Sami Alkafaas, Mohamed I. Elsalahaty, Doha F. Ismail, Mustafa Ali Radwan, Sara Samy Elkafas, Samah A. Loutfy, Rami M. Elshazli, Narjes Baazaoui, Ahmed Ezzat Ahmed, Wael Hafez, Mohanad Diab, Mohamed Sakran, Mohamed T. El-Saadony, Khaled A. El-Tarabily, Hani K. Kamal, Mohamed Hessien

Published in: Cancer Cell International | Issue 1/2024

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.

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Title: The emerging roles of sphingosine 1-phosphate and SphK1 in cancer resistance: a promising therapeutic target
Authors: Samar Sami Alkafaas
Mohamed I. Elsalahaty
Doha F. Ismail
Mustafa Ali Radwan
Sara Samy Elkafas
Samah A. Loutfy
Rami M. Elshazli
Narjes Baazaoui
Ahmed Ezzat Ahmed
Wael Hafez
Mohanad Diab
Mohamed Sakran
Mohamed T. El-Saadony
Khaled A. El-Tarabily
Hani K. Kamal
Mohamed Hessien
Publication date: 01-12-2024
Publisher: BioMed Central
Published in: Cancer Cell International / Issue 1/2024
Electronic ISSN: 1475-2867
DOI: https://doi.org/10.1186/s12935-024-03221-8

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