S1P signaling, its interactions and cross-talks with other partners and therapeutic importance in colorectal cancer

Sattar, Real Sumayya Abdul; Sumi, Mamta P.; Nimisha,; Apurva,; Kumar, Arun; Sharma, Abhay; Ahmad, Ejaj; Ali, Asgar; Mahajan, Bhawna; Saluja, Sundeep Singh

doi:10.1016/j.cellsig.2021.110080

Cited by 11 publications

(9 citation statements)

References 238 publications

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“…Bioactive sphingolipid metabolites could serve as biomarkers for cancer diagnosis, disease progression, and therapeutics (7). Sphingolipids like ceramides, and sphingosine-1-phosphate (S1P), play an important role in regulating tumor cell death (8). There has been considerable advancement in our understanding of SM-associated signaling pathways and their application in cancer therapeutics.…”

Section: Introductionmentioning

confidence: 99%

Dissecting the effect of sphingolipid metabolism gene in progression and microenvironment of osteosarcoma to develop a prognostic signature

et al. 2022

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Sphingolipid metabolism (SM) fuels tumorigenesis and the malignant progression of osteosarcoma (OS), which leads to an unfavorable prognosis. Elucidating the molecular mechanisms underlying SM in osteosarcoma and developing a SM-based prognostic signature could be beneficial in the clinical setting. This study included 88 frozen OS samples to recognize the vital SM-relevant genes in the development of OS utilizing univariate Cox regression. The Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis was conducted on the SM- relevant genes to minimize the risk of overfitting. The prognostic signature was generate utilizing the multivariable Cox regression analysis and was verified in the validation cohort. Moreover, cellular and molecular mechanisms associated with SM have an unfavorable prognosis for OS patients and have been widely studied. Resultantly, an SM-based prognostic risk model was established according to critical prognostic genes (CBS, GLB1, and HACD1), which had an excellent ability to predict the prognosis of OS patients (AUC for the train cohort was 0.887 and AUC for validation cohort was 0.737). The high-risk OS patients identified based on this prognostic signature had significantly poor immune microenvironment, indicated by significantly low immune score (mean=216.290 ± 662.463), reduced infiltrations of 25 immune cells, including NK cells (LogFC= -0.3597), CD8+T cells ((LogFC=-0.2346), Cytolytic activity ((LogFC=-0.1998), etc. The immunosuppressive microenvironment could be due to dysregulated SM of glycolipids. Further, a nomogram was constructed by integrating the SM-based prognostic signature and clinical paraments to facilitate clinical application. The nomogram could accurately predict the prognosis of OS invalids. Collectively, this study clarified the function of SM in the development of OS and helped develop a tool for risk stratification based on SM-related genes with application in clinical settings. The results of our study will aid in identifying high-risk patients and provide individualized treatments.

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Section: Introductionmentioning

confidence: 99%

Dissecting the effect of sphingolipid metabolism gene in progression and microenvironment of osteosarcoma to develop a prognostic signature

et al. 2022

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“…In contrast to ceramides, S1P can modulate multifunctional biological activities in cancer, such as proliferation, migration, inflammation, and angiogenesis. As proposed by Hanahan and Weinberg, S1P is involved in all features of cancer, including sustained proliferative signaling, the evasion of growth inhibitors, resistance to apoptosis, the achievement of uncontrolled replication, angiogenesis, the activation of invasion and metastasis, the reprogramming of energy metabolism, and the evasion of the immune response ( 78 ). The generation of S1P from sphingosine is catalyzed by two SPHK isoforms, namely, SPHK1 and SPHK2.…”

Section: The Value Of Sphingolipid Metabolism In Cancermentioning

confidence: 99%

The key role of sphingolipid metabolism in cancer: New therapeutic targets, diagnostic and prognostic values, and anti-tumor immunotherapy resistance

Wang

et al. 2022

Front. Oncol.

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Biologically active sphingolipids are closely related to the growth, differentiation, aging, and apoptosis of cancer cells. Some sphingolipids, such as ceramides, are favorable metabolites in the sphingolipid metabolic pathway, usually mediating antiproliferative responses, through inhibiting cancer cell growth and migration, as well as inducing autophagy and apoptosis. However, other sphingolipids, such as S1P, play the opposite role, which induces cancer cell transformation, migration and growth and promotes drug resistance. There are also other sphingolipids, as well as enzymes, played potentially critical roles in cancer physiology and therapeutics. This review aimed to explore the important roles of sphingolipid metabolism in cancer. In this article, we summarized the role and value of sphingolipid metabolism in cancer, including the distribution of sphingolipids, the functions, and their relevance to cancer diagnosis and prognosis. We also summarized the known and potential antitumor targets present in sphingolipid metabolism, analyzed the correlation between sphingolipid metabolism and tumor immunity, and summarize the antitumor effects of natural compounds based on sphingolipids. Through the analysis and summary of sphingolipid antitumor therapeutic targets and immune correlation, we aim to provide ideas for the development of new antitumor drugs, exploration of new therapeutic means for tumors, and study of immunotherapy resistance mechanisms.

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“…The dynamic balance between them is called a sphingolipid rheostat. Sphingolipid rheostat is complex, and many enzymes have been shown to be involved in its regulation, including ceramidase, ceramide synthase, sphingosine kinases (SphKs) and phosphorylase [ 2 , 3 ]. SphKs convert sphingosine into S1P, which are critical regulators of cell fate.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis and Biological Activity Testing of Library of Sphk1 Inhibitors

Geng

Chen

et al. 2022

Molecules

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Our team discovered a moderate SphK1 inhibitor, SAMS10 (IC50 = 9.8 μM), which was screened by computer-assisted screening. In this study, we developed a series of novel diaryl derivatives with improved antiproliferative activities by modifying the structure of the lead compound SAMS10. A total of 50 new compounds were synthesized. Among these compounds, the most potent compound, named CHJ04022Rb, has significant anticancer activity in melanoma A375 cell line (IC50 = 2.95 μM). Further underlying mechanism studies indicated that CHJ04022R exhibited inhibition effect against PI3K/NF-κB signaling pathways, inhibited the migration of A375 cells, promoted apoptosis and exerted antiproliferative effect by inducing G2/M phase arrest in A375 cells. Furthermore, acute toxicity experiment indicated CHJ04022R exhibited good safety in vivo. Additionally, it showed a dose-dependent inhibitory effect on the growth of xenograft tumor in nude mice. Therefore, CHJ04022R may be a potential candidate for the treatment of melanoma.

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S1P signaling, its interactions and cross-talks with other partners and therapeutic importance in colorectal cancer

Cited by 11 publications

References 238 publications

Dissecting the effect of sphingolipid metabolism gene in progression and microenvironment of osteosarcoma to develop a prognostic signature

Dissecting the effect of sphingolipid metabolism gene in progression and microenvironment of osteosarcoma to develop a prognostic signature

The key role of sphingolipid metabolism in cancer: New therapeutic targets, diagnostic and prognostic values, and anti-tumor immunotherapy resistance

Design, Synthesis and Biological Activity Testing of Library of Sphk1 Inhibitors

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