Smoothened (SMO) is a transmembrane protein that is overexpressed in lymphoma, and in other cancers. We found that SMO expression is highly induced in doxorubicin-resistant lymphoma cells. In addition, our findings reveal for the first time that SMO is a raft resident protein and that depletion of SMO results in a decrease of multiple cytokine/growth factor receptors in lymphoma and other cancer cells. Furthermore, silencing SMO quantitatively and qualitatively alters cell signaling involved in proliferation and cell survival such as PI3K/AKT. Although SMO localizes in cilia to function as Hedgehog signal transducer, our data support that SMO localizes in lipid rafts, undergoes glycosylated in the presence of doxorubicin and mediates the assembly of a TRAF6 E3 ligase-dependent machinery that enhances AKT signaling, establishing a potential link to chemoresistance.
Currently, we are evaluating whether SMO levels and its activation state directly modulates the properties of lipid rafts with regard to expression of surface receptors or overall lipid raft composition. We are also exploring whether changes in SMO driven compartmentalization of signaling proteins enhances activation of survival pathways contributing to lymphoma progression and chemoresistance.
If our hypothesis is confirmed, our research would provide a first glimpse of different players at the plasma cell membrane level that drive the adaptation process to chemotherapy and would allow the exploration of conceptually novel ways of therapeutic intervention. For the specific case of doxorubicin resistance, this would be the first time that SMO is implicated in lymphoma progression and drug resistance and thereby impacting DLBCL therapy.