Author: Marie Collison ‘25

Cancer is a universally known disease that can be caused by a variety of defects in the genetic code of cells. A very important molecule in the regulation of cellular proliferation is the tumor suppressor protein 53, more commonly known as p53. Mutations or deletions in the p53 gene sequence are detected in the majority of cancers, including several subtypes of lymphomas. Despite the introduction of new therapies, lymphomas involving defects in the p53 pathway are associated with poorer prognosis in patients. A key player in the p53 pathway is the enzyme sphingosine kinase 1 (SK1), encoded by the Sphk1 gene. Loss of SK1 is a major step in the mediation of tumor suppression by p53 and increased SK1 expression and stability has been observed in several different tumoral conditions. These observations make SK1 a potentially promising target for cancer therapies.

Fabiola Valesquez et al. of the Department of Pathology at Stony Brook Medicine published a study in 2023 exploring the effects of SK1 inactivation on tumor growth and progression when cells are deficient in p53. They specifically focused on thymic lymphomas. Using mouse models, the researchers created two lines of p53 knockout (p53KO) mice: one line contained a functional Sphk1 gene (the control) and the other had a dysfunctional Sphk1 gene that was inactivated using a prepared chemical. The researchers took two different approaches to evaluate the effects of targeting SK1 in p53 deficient mice: genetic and pharmacological. They detected thymic lymphoma growth by ultrasound imaging and then harvested the tumors. Analysis of the mRNA revealed a significant decrease in Sphk1 expression in the mice with the inactivated Sphk1 gene. Tumors in these experimental mice were found to have significant growth inhibition, resulting in decreased tumor weights in comparison to the control mice. They concluded that targeting SK1 prevented progression of thymic lymphoma. They also observed an increase in levels of Sph, a lipid that causes programmed cell death of p53KO thymic lymphoma cells, suggesting that SK1 acts to inhibit apoptosis through the Sph signaling pathway. 

This study proposes that SK1 is an important enzyme to consider when researching the growth and development of p53KO lymphomas. The researchers propose that this occurs due to a resulting increase in Sph, which consequently increases apoptotic cell death, inhibiting tumor progression. Further research into these pathways may uncover new therapeutic tactics to better the prognosis of patients with p53KO lymphomas. 

Figure 1 Image of a laboratory mouse like the ones used in this study

[1] Velazquez, F. N., Stith, J. L., Zhang, L., Allam, A., Haley, J. D., Obeid, L. M., Snider, A. J., & Hannun, Y. A. (2023). Targeting sphingosine kinase 1 in p53KO thymic lymphoma. The FASEB Journal, 37(11). https://doi.org/10.1096/fj.202301417r

[2] Image retrieved from: File:Lab mouse mg 3294.jpg – Wikimedia Commons