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. Graphical Abstract

Targeting Sphingosine-1-Phosphate Signaling in Breast Cancer

“…Cancer cells often have abundant SphK1 in the cytoplasm, and S1P production is enhanced [ 161 , 162 ]. In cancer development and progression, S1P “inside-out” signaling plays a critical role, and S1P acts on S1P receptors on the plasma membrane of the cancer cell itself and in the surrounding microenvironment via autocrine and paracrine modes of action [ 29 , 163 ].…”

Garlic bioactive substances and their therapeutic applications for improving human health: a comprehensive review

“…Therefore, garlic and its bioactive constituents have the potential to serve as a beneficial strategy in the prevention and management of specific types of cancer ( 172 , 173 ). Primary anticancer strategies include initiating apoptosis, inhibiting the growth and division of cancer cells, regulating the metabolism of carcinogenic agents, limiting the formation of new blood vessels, and minimizing invasion and metastasis ( 174 , 175 ).…”