Contribution of aberrant lipid signalling to the pathogenesis of Hodgkin´s lymphoma

Introduction: Sphingosine-1-phosphate (SIP) is a pleiotropic lipid mediator which is produced by phosphorylation of sphingosine, a reaction catalysed by the enzyme Sphingosine kinase-1 (SPHK1). SIP has been shown to regulate cell growth, survival, invasion, and angiogenesis, and is up-regulated in many solid tumors such as lung, breast, melanoma, and ovarian cancers where its expression has been shown to modulate multi-drug resistance.

Objectives: These include: profiling the expression of lipid signalling molecules in HL cell lines and primary HL tissue; investigating the contribution of SPHK1 to the generation of SIP in HL; and determining whether the SIP inhibitor, Sphingomab, can reverse the malignant phenotype of HL cell lines.

Results: It has been shown that the expression of SPHK1 is increased in both HL cell lines and in primary HRS cells, and that its inhibition by Dimethylsphingosine and SPHK1 Inhibitor II reduces the proliferation and viability of HL cells. It has been confirmed a marked reduction of SPHK1 RNA expression following treatment with SPHK1 siRNA. Using gene expression profiling, that treatment of the HL cell line, L591, with the SIP inhibitor, Sphingomab, is followed by reversal of many of the transcriptional changes previously described in HL.

Conclusion: S1P/SPHK1 pathway plays a significant role in the pathogenesis of Hodgkin´s lymphoma. Thus direct targeting of important lipid signalling molecules is a novel strategy for development of new types of cancer treatments that could be useful in combination with other treatment strategies