PKC zeta-mTOR Pathway: A New Target for Rituximab Therapy in Follicular Lymphoma.

Previous studies have documented that, in malignant B-cells, Rituximab elicits a complex and not yet totally understood signalling network contributing to its anti-tumour effect. In this context, we investigated the role of protein kinase C zeta, an atypical PKC isoform, in the cellular response to Rituximab. We found that follicular lymphoma cells displayed an increase in PKC zeta expression and activity levels, compared to non malignant B cells, and that this enzyme was a critical regulator of the classical MAPK module by stimulating Raf-1 kinase activity. PKC zeta appeared to be a significant contributor of abnormal mTOR regulation in follicular lymphoma cells through a MAPK-dependent mechanism. Rituximab was found to inhibit the PKC zeta/MAPK/mTOR module in these cells but not in other B-cell lymphomas. Importantly, the expression of a constitutively active form of PKC zeta resulted in an efficient protection of these cells towards Rituximab. Altogether, our study describes a new regulatory component of mTOR pathway in follicular cell lymphoma, and demonstrates that PKC zeta is a target for Rituximab. Therefore, PKC zeta could represent an important parameter for Rituximab efficacy and a promising target for future targeted therapy in follicular lymphoma.