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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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NEOPLASIA

PKC {zeta}–mTOR pathway: a new target for rituximab therapy in follicular lymphoma

Ludivine Leseux1, Guy Laurent1,2, Camille Laurent3, Maxime Rigo1, Amandine Blanc1, Daniel Olive4, and Christine Bezombes1

1 INSERM, Unite 563, Centre de Physiopathologie de Toulouse Purpan, Université Toulouse III Paul-Sabatier, Toulouse; 2 Service d'hématologie, Centre Hospitalier Universitaire (CHU) Purpan, Toulouse; 3 Service d'anatomie et cytologie pathologiques, CHU Purpan, Toulouse; and 4 Immunologie des Tumeurs, Institut Paoli-Calmettes, Faculté de Médecine de Marseille, Université de la Méditerranée, Marseille, France

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 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 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.


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Related Article in Blood Online:

The rituximab-PKC{zeta}/Raf-1/mTOR connection
Benjamin Bonavida
Blood 2008 111: 5-6. [Full Text] [PDF]





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