Abstract
Colorectal carcinoma (CRC) is the leading cause of cancer-related deaths worldwide. Despite advances in prevention and treatment modalities for CRC, rapidly developing resistance to chemotherapy limits its effectiveness. For that reason, it is important to better understand the mechanisms that undergird the process of chemoresistance to enable design of novel anticancer agents specifically targeting malignant properties of cancer cells. Over recent decades, bioactive sphingolipid species have come under the spotlight for their recognized role in cancer development and progression, and the evidence has surfaced to support their role as regulators of anti-cancer drug resistance. Colon cancer is characterized by a shift in sphingolipid balance that favors the production and accumulation of oncogenic species such as sphingosine 1-phosphate (S1P). S1P is known to govern the processes that facilitate cancer cell growth and progression including proliferation, survival, migration, invasion and inflammation. In this review paper, we will give a comprehensive overview of current literature findings on the molecular mechanisms by which S1P turnover, transport and signaling via receptor-dependent and independent pathways shape colon cancer cell behavior and influence treatment outcome in colon cancer. Combining available modulators of S1P metabolism and signaling with standard chemotherapy drugs could provide a rational approach to achieve enhanced therapeutic response, diminish chemoresistance development and improve the survival outcome in CRC patients.
Highlights
Introduction intoSphingosine 1-Phosphate SignalingSphingosine 1-phosphate (S1P), a bioactive lipid mediator, is found in various cancerous tissues as well as in tumor microenvironment (TME)
The intracellular concentration of sphingosine 1-phosphate (S1P) is low and tightly controlled by the balance between its production catalyzed by sphingosine kinases, dephosphorylation back to sphingosine by S1P phosphatases and lipid phosphate phosphatases (LPPs), and its catabolism catalyzed by endoplasmic reticulum enzyme S1P lyase
This study indicates that Sphingosine kinase 1 (SphK1) contributes to metastatic progression of colon cancer by triggering epithelial-mesenchymal transition (EMT) via up-regulation of matrix metalloproteinase-2 (MMP2)/9 expression accompanied by activation of FAK/AKT signaling pathways [57]
Summary
Sphingosine 1-phosphate (S1P), a bioactive lipid mediator, is found in various cancerous tissues as well as in tumor microenvironment (TME). Raising the expression of LPP1 in breast and thyroid cancer cells attenuates tumor growth and suppresses lung metastasis in mice, which could be attributed to inhibition of signaling downstream of G-protein-coupled receptors [9]. Circulating S1P secreted by endothelial cells can promote cancer metastasis by suppressing the activity of cytotoxic T-cells through binding to S1P receptors on the surface of immune cells (Figure 2) [12] Both systemic and tumor S1P are important regulators of local tumor growth; it is systemic. Sphk1-derived S1P promotes mitosis in human cervical carcinoma HeLa cells by binding to and activating S1PR5 on the extracellular side resulting in the downstream activation of intracellular phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway [18]. PI3K/AKT due its ability to couple to different G proteins
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