Expression Profile of Sphingosine Kinase 1 Isoforms in Human Cancer Tissues and Cells: Importance and Clinical Relevance of the Neglected 1b-Isoform

Overview

Journal J Oncol

Specialty Oncology

Date 2022 Dec 19

PMID 36532885

Authors

Hongjie Chen

Nahal Haddadi

Xiaofeng Zhu

Diana Hatoum

Size Chen

Najah T Nassif

Yiguang Lin

Eileen M McGowan

Affiliations

Soon will be listed here.

Abstract

Background: Overexpression of sphingosine kinase 1 (SphK1) is casually associated with many types of cancer, and inhibitors of SphK1 sensitize tumors to chemotherapy. SphK1 is expressed as two major isoforms, SphK1a and SphK1b. To date, no information has been reported on the SphK1 isoform expression profile and its clinical relevance.

Objective: The objective is to examine the expression profile of the SphK1a and SPhK1b isoforms in human cancer and noncancer tissues and cell lines and explore their clinical relevance.

Methods: We used PCR to qualitatively examine the expression profile of these two isoforms in breast, liver, and prostate cancer tissues plus paired adjacent tissues and in 11 cancer and normal cell lines (breast, cervical, bone, prostate, colon, brain, mesothelioma tumor and benign, and human kidney cells).

Results: We found that SphK1a was ubiquitously expressed in all cancer cells and tissues tested; in contrast, SphK1b was only expressed in selective cell types in breast, prostate, and lung cancer.

Conclusions: Our data suggest that SphK1a is important for generic SphK1/S1P functions, and SphK1b mediates specialized and/or unique pathways in a specific type of tissue and could be a biomarker for cancer. This discovery is important for future SphK1-related cancer research and may have clinical implications in drug development associated with SphK1-directed cancer treatment.

Citing Articles

The Role of Sphingolipid Metabolism in Pregnancy-Associated Breast Cancer After Chemotherapy.

Blokhin V, Zavarykina T, Kotsuba V, Kapralova M, Gutner U, Shupik M Biomedicines. 2025; 12(12.

PMID: 39767749 PMC: 11673991. DOI: 10.3390/biomedicines12122843.

Protective Role of Sphingosine-1-Phosphate During Radiation-Induced Testicular Injury.

Wang D, Xu R, Wang Z Antioxidants (Basel). 2024; 13(11).

PMID: 39594464 PMC: 11591009. DOI: 10.3390/antiox13111322.

Unleashing the potential of Genistein and its derivatives as effective therapeutic agents for breast cancer treatment.

Qaed E, Liu W, Almoiliqy M, Mohamed R, Tang Z Naunyn Schmiedebergs Arch Pharmacol. 2024; .

PMID: 39549063 DOI: 10.1007/s00210-024-03579-6.

Targeting Sphingosine 1-Phosphate Metabolism as a Therapeutic Avenue for Prostate Cancer.

Mebarek S, Skafi N, Brizuela L Cancers (Basel). 2023; 15(10).

PMID: 37345069 PMC: 10216412. DOI: 10.3390/cancers15102732.

Expression Profile of Sphingosine Kinase 1 Isoforms in Human Cancer Tissues and Cells: Importance and Clinical Relevance of the Neglected 1b-Isoform.

Chen H, Haddadi N, Zhu X, Hatoum D, Chen S, Nassif N J Oncol. 2022; 2022:2250407.

PMID: 36532885 PMC: 9750787. DOI: 10.1155/2022/2250407.

References

Lim K, Gray A, Pyne S, Pyne N . Resveratrol dimers are novel sphingosine kinase 1 inhibitors and affect sphingosine kinase 1 expression and cancer cell growth and survival. Br J Pharmacol. 2012; 166(5):1605-16. PMC: 3419905. DOI: 10.1111/j.1476-5381.2012.01862.x. View

McGowan E, Lin Y, Chen S . Targeting Chronic Inflammation of the Digestive System in Cancer Prevention: Modulators of the Bioactive Sphingolipid Sphingosine-1-Phosphate Pathway. Cancers (Basel). 2022; 14(3). PMC: 8833440. DOI: 10.3390/cancers14030535. View

Ding Y, Tang Y, Kwok C, Zhang Y, Bevilacqua P, Assmann S . In vivo genome-wide profiling of RNA secondary structure reveals novel regulatory features. Nature. 2013; 505(7485):696-700. DOI: 10.1038/nature12756. View

Hannun Y, Obeid L . Principles of bioactive lipid signalling: lessons from sphingolipids. Nat Rev Mol Cell Biol. 2008; 9(2):139-50. DOI: 10.1038/nrm2329. View

Satyananda V, Oshi M, Tokumaru Y, Maiti A, Hait N, Matsuyama R . Sphingosine 1-phosphate (S1P) produced by sphingosine kinase 1 (SphK1) and exported via ABCC1 is related to hepatocellular carcinoma (HCC) progression. Am J Cancer Res. 2021; 11(9):4394-4407. PMC: 8493375. View

Raza A, Huang W, Takabe K . Advances in the management of peritoneal mesothelioma. World J Gastroenterol. 2014; 20(33):11700-12. PMC: 4155360. DOI: 10.3748/wjg.v20.i33.11700. View

Vadas M, Xia P, McCaughan G, Gamble J . The role of sphingosine kinase 1 in cancer: oncogene or non-oncogene addiction?. Biochim Biophys Acta. 2008; 1781(9):442-7. DOI: 10.1016/j.bbalip.2008.06.007. View

Su Y, Zhang J, Li S, Tan X, Huang J . Relationship of vasculogenic mimicry, SphK1 expression, and Cx43 expression to metastasis and prognosis in colorectal cancer. Int J Clin Exp Pathol. 2020; 11(11):5290-5299. PMC: 6963043. View

Maczis M, Maceyka M, Waters M, Newton J, Singh M, Rigsby M . Sphingosine kinase 1 activation by estrogen receptor α36 contributes to tamoxifen resistance in breast cancer. J Lipid Res. 2018; 59(12):2297-2307. PMC: 6277156. DOI: 10.1194/jlr.M085191. View

10.

Sauer L, Nunes J, Salunkhe V, Skalska L, Kohama T, Cuvillier O . Sphingosine kinase 1 inhibition sensitizes hormone-resistant prostate cancer to docetaxel. Int J Cancer. 2009; 125(11):2728-36. DOI: 10.1002/ijc.24640. View

11.

Pyne N, McNaughton M, Boomkamp S, MacRitchie N, Evangelisti C, Martelli A . Role of sphingosine 1-phosphate receptors, sphingosine kinases and sphingosine in cancer and inflammation. Adv Biol Regul. 2015; 60:151-159. DOI: 10.1016/j.jbior.2015.09.001. View

12.

Ikarashi M, Tsuchida J, Nagahashi M, Takeuchi S, Moro K, Toshikawa C . Plasma Sphingosine-1-Phosphate Levels Are Associated with Progression of Estrogen Receptor-Positive Breast Cancer. Int J Mol Sci. 2021; 22(24). PMC: 8703495. DOI: 10.3390/ijms222413367. View

13.

Loveridge C, Tonelli F, Leclercq T, Lim K, Long J, Berdyshev E . The sphingosine kinase 1 inhibitor 2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole induces proteasomal degradation of sphingosine kinase 1 in mammalian cells. J Biol Chem. 2010; 285(50):38841-52. PMC: 2998105. DOI: 10.1074/jbc.M110.127993. View

14.

Cuvillier O, Pirianov G, Kleuser B, Vanek P, Coso O, Gutkind S . Suppression of ceramide-mediated programmed cell death by sphingosine-1-phosphate. Nature. 1996; 381(6585):800-3. DOI: 10.1038/381800a0. View

15.

Ng M, Wadham C, Sukocheva O . The role of sphingolipid signalling in diabetes‑associated pathologies (Review). Int J Mol Med. 2017; 39(2):243-252. PMC: 5358714. DOI: 10.3892/ijmm.2017.2855. View

16.

Sukocheva O, Wang L, Albanese N, Pitson S, Vadas M, Xia P . Sphingosine kinase transmits estrogen signaling in human breast cancer cells. Mol Endocrinol. 2003; 17(10):2002-12. DOI: 10.1210/me.2003-0119. View

17.

Ulitsky I, Shkumatava A, Jan C, Subtelny A, Koppstein D, Bell G . Extensive alternative polyadenylation during zebrafish development. Genome Res. 2012; 22(10):2054-66. PMC: 3460199. DOI: 10.1101/gr.139733.112. View

18.

Sukocheva O, Furuya H, Ng M, Friedemann M, Menschikowski M, Tarasov V . Sphingosine kinase and sphingosine-1-phosphate receptor signaling pathway in inflammatory gastrointestinal disease and cancers: A novel therapeutic target. Pharmacol Ther. 2019; 207:107464. DOI: 10.1016/j.pharmthera.2019.107464. View

19.

Pitson S, DAndrea R, Vandeleur L, Moretti P, Xia P, Gamble J . Human sphingosine kinase: purification, molecular cloning and characterization of the native and recombinant enzymes. Biochem J. 2000; 350 Pt 2:429-41. PMC: 1221270. View

20.

Dong Y, Xia M, Wang L, Cui S, Li Q, Zhang J . Spatiotemporal Expression of SphK1 and S1PR2 in the Hippocampus of Pilocarpine Rat Model and the Epileptic Foci of Temporal Lobe Epilepsy. Front Cell Dev Biol. 2020; 8:800. PMC: 7578367. DOI: 10.3389/fcell.2020.00800. View