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 signaling network contributing to its antitumor effect. In this context, we investigated the role of protein kinase C zeta(PKC 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 with nonmalignant 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 folilcular 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 toward 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.