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Blood, 1 January 2008, Vol. 111, No. 1, pp. 285-291.
Prepublished online as a Blood First Edition Paper on September 12, 2007; DOI 10.1182/blood-2007-04-085092.
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Submitted April 16, 2007
Accepted August 10, 2007
PKC zeta-mTOR pathway: a new target for Rituximab therapy in follicular lymphoma
Ludivine Leseux, Guy Laurent, Camille Laurent, Maxime Rigo, Amandine Blanc, Daniel Olive, and Christine Bezombes*
Departement d'Oncogenese, Signalisation et Innovation therap, INSERM, Unite 563, Centre de Physiopathologie de Toulouse Purpan, Univ. Toulouse III Paul-Sabatier, Toulouse, France
Service d'hematologie, CHU Purpan, Toulouse, France
Service d'anatomie et cytologie pathologiques, CHU Purpan, Toulouse, France
Immunologie des Tumeurs, Institut Paoli-Calmettes, Faculte de Medecine de Marseille, Universite de la Mediterranee, Marseille, France
* Corresponding author; email: christine.bezombes-cagnac{at}toulouse.inserm.fr.
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.
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