By investigating lipid-mediated cell signalling pathways that contribute to cancer and other diseases, research in our laboratory is breaking new ground. In particular, our work is concerned with the sphingolipid pathway, which can trigger increased cell survival, increased cell proliferation, and new blood vessel formation; three of the classic hallmarks of cancer. Indeed, we and others have established that sphingosine kinase, a central enzyme in the sphingolipid pathway, plays an important role in many different cancers, and is an attractive target for anti-cancer therapy.
Our research focuses on three main areas:
- Understanding the molecular mechanisms regulating sphingosine kinase in cancer
- Developing agents that target sphingosine kinase, or its regulation, as anti-cancer agents
- Defining the downstream pathways important for sphingolipid-mediated cancer cell signalling
Current research projects
- Defining the role of novel binding proteins in oncogenic signalling by sphingosine kinase: We have previously established that localisation of sphingosine kinase to the plasma membrane is critical for oncogenic signalling by this enzyme. Now we are seeking to understand how this localisation of sphingosine kinase is regulated via characterisation of the roles of a number of proteins that associate with this enzyme. This may identify new targets for anti-cancer therapy.
- Characterising the anti-cancer activity of novel sphingosine kinase inhibitors: We recently developed novel chemical inhibitors of sphingosine kinase that show exciting anti-cancer activity in various cancer models. Now we are further assessing and developing the existing, and second-generation inhibitors as anti-cancer and chemotherapy-sensitising agents.
- Characterising downstream effectors of sphingosine and determining their role in cancer biology: Cancer cells adopt multiple molecular mechanisms to evade cell death, one of which is the pro-survival 14-3-3 proteins. We have recently identified that the survival function of the 14-3-3 proteins is regulated by sphingosine. We are elucidating the molecular mechanisms involved in this new signalling pathway with the aim of harnessing this process to develop new anti-cancer agents.
Selected recent publications
Pham DH, Powell JA, Gliddon BL, Moretti PAB, Tsykin A, Van der Hoek M, Kenyon R, Goodall GJ & Pitson SM (2014) Enhanced expression of transferrin receptor 1 contributes to oncogenic signalling by sphingosine kinase 1. Oncogene, in press.
Wallington-Beddoe CT, Powell JA, Tong C, Pitson SM, Bradstock KF & Bendall LJ (2014) Sphingosine kinase 2 promotes acute lymphoblastic leukemia by enhancing MYC expression. Cancer Res, in press.
Carr JM, Mahalingam S, Bonder CS & Pitson SM (2013) Sphingosine kinase 1 in viral infections. Rev Med Virol 23, 73–84.
Chan H & Pitson SM (2013) Post-translational regulation of sphingosine kinases. Biochim Biophys Acta - Mol Cell Biol Lipids 1831, 147–156.
Neubauer HA & Pitson SM (2013) Roles, regulation and inhibitors of sphingosine kinase 2. FEBS J 280, 5317–5336.
Carr JM, Kua T, Calvert JK, Zebol JR, Beard MR & Pitson SM (2013) Reduced sphingosine kinase 1 activity in dengue virus type-2 infected cells can be mediated by the 3’untranslated region of dengue virus type-2 RNA. J Gen Virol 94, 2437–2448.